4-substitutedamino-phenylacetic acids and derivatives thereof

ABSTRACT

As a group of extraordinarily active anti-inflammatory agents, 4-aminophenyl acetic acids substituted at the nitrogen and phenyl positions, and derivatives thereof, e.g., 3-chloro-4-piperidinoAlpha -methyl acetic acid, 3-methyl-4-piperidino- Alpha -methyl acetic acid, and 4-piperidino-naphthyl acetic acids.

Unite States Borck et a1.

[ June 13, 1972 4-SUBSTITUTEDAMINO- PHENYLACETIC ACIDS AND DERIVATIVES THEREOF [72] Inventors: Joachim Borck; Johann Dahm; Volker Koppe; Josef Kramer; Gustav Shorre; J. W. Hermann Hovy; Ernst Schorscher, all of Darmstadt, Germany [73] Assignee: E. Merck A. G., Darmstadt, Germany [22] Filed: July 22, 1968 [21] Appl. No.: 746,326

[30] Foreign Application Priority Data July 22, 1967 Germany ..M 74881 Jan. 8, 1968 Feb. 23, 1968 March 1, 1968 Germany ..M 77429 [52] US. Cl ..260/239 BF, 260/239 A, 260/239 E,

260/243 B, 260/246, 260/247.1, 260/247.2 R, 260/2472 A, 260/247.2 B, 260/2475 R, 260/247.7 A, 260/247.7 H, 260/268 C, 260/268 PH, 260/293.62, 260/293.64, 260/293.67, 260/293.68, 260/293.69, 260/293.7l, 260/293.72, 260/293.73, 260/293.75, 260/293.76, 260/293.77, 260/293.79, 260/29381, 260/293.82, 260/293.83, 260/293.84, 260/306.7, 260/306.8 R, 260/307 F, 260/307 H, 260/309.7, 260/326.3, 260/326.5 S, 260/326.5 SF, 260/326.5 E, 260/326.5 G, 260/326.5 L, 260/326.5 N, 260/465 D, 260/465 E, 260/470, 260/471 R,

[5 6] References Cited UNITED STATES PATENTS 3,252,970 5/1966 Huebner ..260/239 3,385,852 5/1968 Casadio ..260/246 OTHER PUBLICATIONS Norman et al., J. Chem. Soc 1963, (Nov.), 5431- 6.

Primary Examiner-Henry R. .liles Assistant ExaminerG. Thomas Todd Att0rneyMillen, Raptes & White [5 7] ABSTRACT As a group of extraordinarily active anti-inflammatory agents, 4-aminophenyl acetic acids substituted at the nitrogen and phenyl positions, and derivatives thereof, e.g., 3-chloro-4- piperidino-a-methyl acetic acid, 3-methyl-4-piperidino-amethyl acetic acid, and 4-piperidino-naphthyl acetic acids.

144 Claims, No Drawings 4-SUBSTl'lU'l'EDAMINO-Pl-IENYLACE'I'IC ACIDS AND DERIVATIVES THEREOF This invention relates to substituted 4-aminophenylacetic acids and the derivatives thereof.

According to an object of one aspect of this invention, there are provided a novel group of chemical compounds as well as processes for their manufacture.

According to an object of another aspect of this invention, there are provided novel pharmaceutical compositions for effecting anti-inflammatory, and other therapeutic activities.

Upon further study of the specification and claims, other objects and advantages of the present invention will become apparent To attain these compounds, there are provided compounds of the following formula:

In the above formula and in all fonnulas set out hereinbelow, the variables have the following meanings, unless otherwise expressly indicated in individual formulas:

R and R being identical or different, represent H or alkyl of one to four carbon atoms;

R represents F, Hal, CP OH, NO,, CN, R R SH, SR

NR,COR,,, NR R SO,NR,R SORi or $0,11 and under special circumstances, R, can represent H;

R,, R and R represent H; with the provisions that one each of these residues can also represent F, Hal, R CR or SR,,; and the residues R and R together can also represent a tetramethylene optionally containing one to two double bonds; the latter special case wherein R and R represent tetramethylene optionally containing one to two double bonds, R, can also be H and R can represent H, F, Hal, CF OH, N0 CN, R CR SR NR,COR,,, NR R SO NR,R,, SOR or SO R R and R represent linear or branched alkyl of one to seven carbon atoms, or together a linear or branched alkylene chain of two to 14 carbon atoms which chain can optionally be interrupted by an oxygen or sulfur atom, the residue R, and R being identical or different;

R, represents alkyl of one to four carbon atoms;

R is acyl (preferably acetyl) or a hydrocarbon residue (preferably methyl or phenyl);

R represents R represents alkylidene of one to seven carbon atoms; and

R represents alkyl of one to seven carbon atoms, wherein the residues R and/or R can contain one or more additional C C (double) bonds or C EC (triple) bonds, and wherein these residues can also be connected with each other in the form of a ring directly or by way of an oxygen or sulfur atom;

R is an optionally substituted hydrocarbon residue (preferably alkyl of one to four carbon atoms);

R, and R represent H or an optionally substituted hydrocarbon residue (preferably alkyl of one to four carbon atoms or phenyl; the residues R and R being identical or different);

R is a (CH,),CHX X, group which can, if desired, contain an additional double bond; a -(CH ),X, group which can, if desired, contain one or two additional double bonds; or 3-butenyl, 3-butynyl, l,3-butadienyl or 1- buten-3-ynyl;

A represents COOA,, CONA A CONA C( NOH)OH or eh;

DNS

A A, and A represent H; an alkyl or cycloalkyl group which optionally contains one to two CC unsaturated bonds and/or an OH group and/or an NH, group and/or which is interrupted by 0 once to three times and/or interrupted by Y and/or which is branched, this group being of respectively up to 12 carbon atoms; A5NA4; phenyl or aralkyl of a total of six to l4 carbon atoms (the residues A,, A, and 1% being identical or different);

A, is alkylene of up to six carbon atoms, optionally inter rupted by O or Y;

A, is alkylene of one to six carbon atoms;

B is an anion, preferably Hal B, is OH, esterified OH, OM or Hal;

B is alkyl of one to four carbon atoms substituted by 8,;

D is COO or CoNA Hal is Cl, Br or I;

L is a group oxidizable to a carboxyl group, such as, ad vantageously, CHO, cinon, CH l-alkenyl, l-alkynyl, l,2-dihydroxyalkyl or l-oxoalkyl of preferably up to four carbon atoms, respectively;

M represents metal, especially alkali metal, preferably Li,

CdR,,, Zn-R or MgHal;

M is H or metal, advantageously alkali or alkaline earth metal, preferably Na or K;

O represents H or M;

X represents a residue that can be split off with M as MX, and is preferably Hal or a sulfuric or sulfonic acid residue;

X is a residue substitutable by an amino group, especially Hal, OH, acyloxy, a secondary or tertiary amino group, a sulfuric acid residue, an alkylsulfuric acid residue (wherein the alkyl group is of preferably one to four carbon atoms), or a sulfonic acid residue;

X, represents Hal, OH, acyloxy or alkoxy of preferably respectively up to four carbon atoms, a sulfuric acid residue or a sulfonic acid residue;

X is OH, SH, O-acyl or S-acyl of preferably up to four carbon atoms each, or X;

X, and X represent each OR SR, NR R or together also 0 or E (the residues X, and X being identical or different);

X,, represents a residue which can be split off with H as HX,,, especially Hal; or OH, SH or NH optionally substituted by alkyl, acyl, alkysulfonyl or alkoxysulfonyl of respectively up to four carbon atoms;

X and X represent Hal or OH optionally substituted by alkyl, acyl, alkylsulfonyl or alkoxysulfonyl of preferably respectively up to four carbon atoms (the residues X and X being identical or different);

Y represents S, NH, N-alkyl of one to six carbon atoms optionally substituted by OH, N-phenyl or N-phenyl-alkyl of seven to 10 carbon atoms;

It has been discovered that substituted 4-aminophenylacetic acids and the derivatives thereof, of Formula I, as well as the salts thereof with acids or bases, the quaternary ammonium salts thereof and the anhydrides thereof exhibit utstanding anti-inflammatory activities, as well as good analgesic and anti-pyretic activities, all the compounds being also physiologically compatible. In addition, these compounds also exhibit bacteriostatic, bactericidal, antiprotozoal, diuretic, bloodsugar-lowering, choleretic, cholesterol-level-lowering, and radiation-protective effects.

Thus, the following effect relationships resulted with respect to several of the compounds of the present invention as compared, for example, with the compound lbufenac (pisobutylphenylacetic acid), an antiphlogistic of similar constitution, in a UV erythema test on guinea pigs:

Substance Effect Relationship lbufenac (Comparison Substance) l 3-Chloro-4-piperidino-a-methyl-phenylacetic acid (A) 300-500 3-Bromo-4-piperidino-a-methyl-phenylacetic acid (B) 300-500 4-Piperidino-a-methyl-naphthyl-l -acetic acid 300-500 Ethyl ester of 3-chloro-4-piperidino-a-methylphenylacetic acid l-200 2'-Diethylarninoethyl ester of 3-chlor0-4- piperidino-a-methyl-phenylacetic acid (C) l00-200 Methyl ester of 4-piperidino-a-methylnaphthyl-l-acetic acid (D) 100-200 Ethyl ester of 4-piperidino-a-methyl-naphthyll-acetic acid 100-200 3-M ethyl-4-piperidino-a-n'lethyl-phenylacetic acid (E) 100-200 3-Amino-4-piperidino-a-methyl-phenylacetic acid (F) 100-200 2'-Diethylaminoethyl ester of 3-chloro-4- piperidino-a-methyl-phenyl-acetic acid fumarate 100-200 2-Ethylbutyl ester of 3-chloro-4-piperidin0-crmethyl-phenylacetic acid (G) 100-200 2'-Dimethylaminoethyl ester of 3-chloro-4- piperidino-a-methyl-phenylacetic acid fumarate 100- 200 4-Piperidino-a-ethyl-naphthyl-l -acetic acid 100-200 2,3-Dichlor0-4-piperidino-a-methylphenylacetic acid [00-150 Methyl ester of 4-piperidino-naphthyl-l-acetic acid hydrochloride 30-l00 Ethyl ester of 4-Piperidino-naphthyl-l-acetic acid 30-100 2'-Diethylaminoethyl ester of 4-piperidinonaphthyl-l-acetic acid 30-100 2-M ethyl-3-chloro-4-piperidino-a-methylphenylacetic acid 30-100 2-Diethylaminoethyl ester of 4-piperidino-amethyl-naphthyl-l-acetic acid 30-100 In this connection, the substances of this invention exhibit approximately the same acute toxicity as the comparison substance (on mice).

The compounds of this invention also show marked advantages over other anti-inflammatories of entirely different structures. Thus, the following comparative relationships were determined with phenylbutazone (l,2-diphenyl-4-n-butyl-3,5- pyrazolidinedione) with the compounds of this invention exhibiting the same or lower toxicities:

writhing Kaolin-Edema Test Test (Mouse) (Rat) Phenylbutazone (comparison substance) 1 l A l 6 20 B 4 10 C 7 3 D E l0 [0 F I0 G 5 References to the pharmacological tests are as follows: UV erythema test: Arch. int. pharmacodyn, I16, 26l (1958); writhing test (analgetischer Schleifiest"):

Proc. Soc. exp. Biol. (NY) 95, 729 1959);

Kaolin edema test:

Ann. NY. Acad. Sci. 86, 263 1960).

Generally, the compounds of the present invention can be used in all instances where it is customary to employ lbufenac or lndomethacin. More specifically, diseases such as inflammatory states of the joints and the muscular system, rheumatic fever, chronic rheumatic arthritis, periarthritis, and neuritis, can successfully be treated with the compounds of this invention.

As compared to the conventional antiphlogistic indomethacin l-p-chlorobenzoyl-2-methyl-5-methoxy-indolyl- 3-acetic acid), the compounds of the present invention are distinguished by a generally substantially lower toxicity and a higher therapeutic index. Thus, compound 8, for example, is about 10 times as effective as indomethacin on the UV erythema of the guinea pig, but exhibits only about one-thirtieth of the acute toxicity of indomethacin (on mice).

Aside from the compounds of general Formula I, this invention embraces the following subgeneric preferred groups of compounds of Formula 1, as well as the salts thereof with acids or optionally bases, the quaternary ammonium salts thereof and optionally the anhydrides thereof, wherein the residues not set forth in detail have the above-indicated meanings, but wherein:

1. R, and R, represent H, and

A represents COOH;

2. R,, and R represent H, and

A has the above-indicated meanings, but does not represent COOH;

3. R and R, together represent a tetramethylene optionally containing one to two double bonds, and

R, and R represent H, and wherein one of the residues R and R, can also be P, Hal, CF}, OH, N0 CN, R, 0R SR NR,-COR,, NR R SO NR,R,, SOR or SO R 4; R represents H, and one of the residues R and R is H and the other one is F, Hal, R CR or SR 5. A represents COOH;

6. R, is H, methyl, ethyl or propyl;

7. R is H;

8. R R, and R each represents H;

9. R R R and R each represents H;

10. R and R together represent -CH CHCH l l. R represents SOR or SO R l 2. R represents F, Cl, Br, R NH, or N0 13. R, and R together represent tetramethylene, pentamethylene, hexamethylene or 3-oxapentamethylene;

14. R and R being identical or difierent, each represents alkyl of one to six carbon atoms;

15. A represents COOA,;

16. R represents H, methyl, ethyl or propyl, and

A represents COOA,;

17. R is H, and

A represents COOA,;

18. R R, and R each represents H, and

A represents COOA,;

19. R R R and R each represents H, and

A represents COOA,;

20. R, and R together represent CH CH-CH CH-, and

A represents COOA,;

2i. R isS0R,orSO R and A represents COOA 22. R, is F, Cl, Br, R NH or N0 and A is COOA,;

23. R, and R together represent tetramethylene, pentarnethylene, hexamethylene or 3-oxapentamethylene, and

A represents COOA,-,

24. R, and R being identical or different, each represents alkyl of one to six carbon atoms,

and A represents COOA,;

25. R, is H, methyl, ethyl or propyl,

R is H or methyl,

R is Cl, Br, R NH, or N or (if R, and R, together are CH CHCH CH) H,

R and R, H or together CH CH-CH CH-,

R is H, methyl, C1 or Br,

R, and R, together represent tetramethylene, pentamethylene, hexamethylene or 3-oxapentamethylene, and

A represents COOA,;

26. R, is H, methyl, ethyl or propyl,

R is H or methyl,

R is Cl, Br, R NH, or N0 or (in case R, and R together are CH CHCH CH) H,

R, and R each are H or together CH CHCH R represents H, methyl, Cl or Br,

R, and R together are tetramethylene, pentamethylene,

hexamethylene or 3-oxapentamethylene,

A is COOA,,

A, is H, alkyl of one to six carbon atoms, dialkylaminoalkyl of four to nine carbon atoms, or A .,NA.,,

A, is tetramethylene, pentamethylene, 3-oxapentamethylene, 3-(methylaza)-pentamethylene or 3-(2- hydroxyethylaza)-pentamethylene, and

27. R, is H, methyl, ethyl or propyl,

R, is H or methyl;

R is Cl, Br, R NH, or NO, or (in case R, and R together represent CH CHCH CH) H,

R, and R each represents H or together they represent CH CH-CH CH,

R is H, methyl, Cl or Br,

R, and R, together represent tetramethylene, pentamethylene, hexamethylene or 3-oxapentamethylene,

A represents COOA,, and

A, is H or alkyl of one to six carbon atoms;

28. R,, R and R each is H, and

A is COOH;

29. R, represents preferably methyl, ethyl or propyl,

R R,, R and R each represents H, and

A is COOH;

R is halogen, preferably C1 or Br, N0 SCH SC H or alkyl of one to four carbon atoms, and

A is COOH;

30. R and R each is H,

R, and R, together represent a pentamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A represents COOH;

31, R,, R, and R each represents H,

R, and R together represent a pentamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A represents COOH;

32, R, is preferably methyl, ethyl or propyl,

R R R and R each is H,

R halogen, preferably C1 or Br, N0 SCH SC,H or alkyl of one to four carbon atoms,

R, and R together represent a pentamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOH;

33. R and R each is H,

R, and R together represent a hexamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOH;

34. R, R and R, is H,

R, and R, together represent a hexamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOH;

34. R R, and R is H,

R, and R together represent a hexamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOH;

35. R, is preferably methyl, ethyl or propyl,

R,, R.,, R and R each is H,

R, is halogen, preferably Cl or Br, N0 SCH SC H, or

alkyl of one to four carbon atoms,

R, and R together represent a hexamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOH;

36. R and R each is H,

R, and R together represent a tetramethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOH;

37. R R and R each is H,

R, and R together represent a tetramethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOH;

38. R, preferably represents methyl, ethyl or propyl,

R R R and R each is H,

R, is halogen, preferably Cl or Br, N0 SCH SC H, or

alkyl of one to four carbon atoms,

R, and R, together represent a tetramethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOH;

39. R, and R each is H,

R, and R being identical or different, represent alkyl of one to six carbon atoms, and

A is COOH;

40. R R and R each is H,

R, and R, being identical or different, represent alkyl of one to six carbon atoms, and

A is COOH;

41. R, is preferably methyl, ethyl or propyl,

R R R and R each is H,

R, is halogen, preferably C] or Br, N0 SCH,, SC H, or

alkyl of one to four carbon atoms,

R, and R being identical or different, represent alkyl of one to six carbon atoms, and

A is COOH;

42. R.,, R and R each is H,

A is other than COOH;

43. R, is preferably methyl, ethyl or propyl,

R R R and R each is H,

R halogen, preferably Cl or Br, N0 SCH SC H or alkyl of one to four carbon atoms, and

A is COOA,,

A, is other than H;

44. R, and R each is H, and

R, and R together represent a pentamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms,

A is other than COOH;

45. R.,, H and R each is H, and

R, and R together represent a pentamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms,

A is other than COOH;

46. R, is preferably methyl, ethyl or propyl,

R R R and R each is H,

R, is halogen, preferably Cl or Br, N0 SCH SC, H or alkyl of one to four carbon atoms,

R, and R together represent a pentamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOA,,

A, is other than H;

47. R and R each is H, and

R, and R, together represent a hexamethylene chain optionally monol or disubstituted by alkyl of one to four carbon atoms,

A is other than COOH;

48. R,, R, and R, each is H, and

R, and R, together represent a hexamethylene chain optionally monoor disubstituted by alkyl one to four carbon atoms,

A is other than COOH;

49. R, is preferably methyl, ethyl or propyl,

R R,, R, and R each is H,

R, is halogen, preferably Cl or Br, N SCI-l SC,H, or

alkyl of one to four carbon atoms,

R, and R, together represent a hexamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOA,,

A, is other than H;

50. R, and R, each is H, and

R, and R, together represent a tetramethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms,

A is other than COOH;

51. R,,, R, and R, each is H, and

R, and R, together represent a tetramethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms,

A is other than COOH;

52. R, is preferably methyl, ethyl or propyl,

R,, R,, R, and R, each is H,

R, is halogen, preferably C1 or Br, N0 SCH,, SC H, or

alkyl of one to four carbon atoms, and

R, and R, together represent a tetramethylene chain op tionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOA,,

A, is other than H;

53. R, and R, each is H, and

R, and R, being identical or different, represent alkyl of one to six carbon atoms,

A is other than COOH;

54. R,, R, and R each is H, and

R, and R, being identical or different, represent alkyl of one to six carbon atoms,

A is other than COOH;

55. R, is preferably methyl, ethyl or propyl,

R,, R.,, R, and R, each is H,

R, is halogen, preferably C] or Br, N0 SCH SC H, or

alkyl of one to four carbon atoms,

R, and R, being identical or different, are alkyl of one to six carbon atoms, and

A is COOA,,

A, is other than H;

56. R, and R, together represent CH CHCH= CH, and

R, is H;

57. R, is preferably methyl, ethyl or propyl,

R and R, is H,

R is H, halogen, preferably Cl or Br, N0 SCH,, SC,H,or

alkyl of one to four carbon atoms,

R, and R, together are CH CHCH CH, and

A is COOA,;

5 8. R, and R, together represent CH CHCH CH, and

R, and R, together represent a pentamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms;

59. R, is preferably methyl, ethyl or propyl,

R, is H,

R, is H, halogen, preferably CI or Br, NO,, SCH,,, SC,H,, or

alkyl of one to four carbon atoms,

R, and R, together represent CH CHCH CH,

R, and R together represent a pentamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOA,;

60. R, and R, together represent CH CHCH CH, and

R, and R, together represent a hexamethylene chain optionally mono or disubstituted by alkyl of one to four carbon atoms;

61. R, is preferably methyl, ethyl or propyl,

R, is H,

R, is H, halogen, preferably Cl or Br, N0 SCH,, SC H, or

alkyl of one to four carbon atoms,

R, and R, together represent CH CHCH CH,

R, and R together represent a hexamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOA,;

62. R., and R,, together represent CH CHCH CH, and

R, and R together represent a tetramethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms;

(63) R, is preferably methyl, ethyl or propyl,

R is H,

R, is H, halogen, preferably C] or Br, N0 SCH,, SC H, or

alkyl of one to four carbon atoms,

R,, and R, together represent CH CHCH CH,

R, and R, together represent a tetramethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOA,;

64. R and R, together are CH CHCH CH, and

R, and R, being identical or different, represent alkyl of one to six carbon atoms;

65. R, is preferably methyl, ethyl or propyl,

R, is H,

R, is H, halogen, preferably Cl or Br, N0 SCH,, SC-,H,, or

alkyl of one to four carbon atoms,

R, and R, together represent CH CHCH CH,

R, and R being identical or different, represent alkyl of one to six carbon atoms, and

A is COOA,,

66. R, is H one of the residues R, and R, is H and the other is F, Hal, R

OR, or SR and A is COOA,;

67. R, is preferably methyl, ethyl or propyl,

R and R is each H,

R, is halogen, preferably Cl or Br, N0 NH,, SCH,, SC H,

or alkyl of one to four carbon atoms,

one of the residues R, and R, is H and the other is F, Hal, R

OR, or SR,, and

A is COOA,;

68. R is H,

one of the residues R, and R, is H and the other is F, Hal, R

OR or SR,, and

R, and R, together represent a pentamethylene chain 0ptionally monoor disubstituted by alkyl of one to four carbon atoms;

69. R, is H,

one of the residues R, and R, is H and the other is F, Hal, R,,,

OR, or SR,,,

R, and R, together represent a pentamethylene chain optionally monoor disubstituted by alkyl of one to four carbon atoms, and

A is COOA,;

70. R, is preferably methyl, ethyl or propyl,

R, and R, is H R, is halogen, preferably Cl or Br. N0 NH,, SCH,, SC,H,

or alkyl or one to four carbon atoms.

one of the residues R, and R is H and the other is l. Hal. R,,,

OR, or SR R, and R together represent a pentamethylene chain optionally monol or disubstituted by alkyl of one to four carbon atoms, and

tionally the anhydrides thereof, the following steps are conducted:

a. If carboxylic acids of Formula 1 (A COOH) are to be A is COOA obtained, functional acid derivatives of such carboxylic acids, 71. R is H, 5 such as, in particular, amides, thioamides, thioesters, esters, one of the residues R and R is H and the other is F, Hal, R hydrazides, acid halogenides, azides, anhydrides, iminoesters, OR or SR,,, and amidines, hydroxamic acids, nitriles, trihalogen methanes, R, and R together represent a hexamethylene chain opacid iminohalogenides, are saponified in a neutral, acidic or tionally monoor disubstituted by alkyl of one to four caralkaline medium, or in particular, tert.alkyl esters, such as bon atoms; 10 tert.-butyl esters, are therrnolytically decomposed, or 72. R, is H, b. compounds of Formula 2 one of the residues R, and R is H and the other is F, Hal, R 2 2 R or 5 are oxidized, or R, and R together represent a hexamethylene chain opdiazoketone of Formula 3 tionally monoor disubstituted by alkyl of one to four car- 1 2 3 bon atoms and is rearranged under the conventional conditions of a Wolff A i COOA; rearrangement in the presence of A OH, A A NH, A NH or 73. R, is preferably methyl, ethyl or propyl, NHZOH, or R2 and R4 each is H, d. an organometalhc compound of Formula 4 R is halogen, preferably Cl or Br, N0 NH SCH, SC,H 4

or alkyl of one to four carbon atoms, reacted carbon dloxldei or one of the residues R and R is H and the other is F, Hal, R a haloketone of Formula 5 0R9 or SR9, Z-COCR ,R Hal 5 R1 and R8 together represent a hexamethylene chain is rearranged under the conventional conditions of a Fawortionally monoor disubstituted by alkyl of one to four carrearrangement or bon atoms and f. a compound of Formula 6 or 7 A is COOA,; ZPBI 6 74. R, is H, ZC HR2B2 7 one of the residues R and R is H and the other is F, Hal, R reacted i cal-bon {nonPXlde or 0R9 or SR9 and g. a malonic acid derivative of Formula 8 R, and R together represent a tetramethylene chain op- A tionally monoor disubstituted by alkyl of one to four carbon atoms; COOH 8 75. R, is H, one of the residues R and R is H and the other is F, Hal, R 15 decarboxylatgd or CR9 or SR9 h. a ,B-keto acid derivative of Formula 9 R, and R, together represent a tetramethylene chain op- RPA tionally monoor disubstituted by alkyl of one to four carbon atoms, and 40 9 A is COOA,; 76. R, is preferably methyl, ethyl or propyl, 1s to an acld cleavage pr0ceS.S or I R and R. is each H l. a compound of Formula 1 wherein there are additionally is g p y Cl or 2 L SCHa Z s Eresent one or more groups substitutable or reducible by ydrogen and/or C-C multiple bonds, such as, in particular, or alkyl of one to four carbon atoms, those compounds of Formula I one of the residues R and R is H and the other is F, Hal, R wherein or R to R and A have the previously indicated meanings R8 together f F a tetramethylene Cham but wherein at least one of these residues contains one or tionally monoor disubstituted by alkyl ofone to four carmore halogen atoms and/or one or more OH SH NH2 groups P atoms and and/or OH, SH or NH, groups substituted by hydrocarbon EZ residues and/or one or more C O and/or C 5 groups 4 i onggf thesrlisidueis R and R is H and the other is F, Hal, R 22:48: 3. i ggt zg gri s s C double bonds 9 or an r R, and R being identical or different, represent alkyl of one 3522 5:3 2:32 fggfiit fi g an alkyhdene group to carbon atoms; R is Hal, 0H, SH, NH,, or OH, SH or NH substituted by 78. R 15 H, hydrocarbon residues and/or wherein the benzene nucleus gg s gj R5 and R8 H and the other is carries additionally in the 2-, 3-, 5- and/or 6-position halogen 9 or t atoms or diazonium salt groupings and/or if R, and R 1 a bemg ldemlca-l or different, represent alkyl of one together represent a tetramethylene group optionally contain- P 51X Carbon atoms and ing one to two double bonds additionally one or more A15 CoOAli halogen atoms and/or diazonium salt groupings are provided 1 is Pf y methyl, ethyl, P PY on this tetramethylene group and/or wherein A is represented 2 'f 4 15 by a benzyl ester or benzyl amide or a benzyl-equivalent ester 3 15 li i ff p tf y b Br, 2 z SCHa, SC2H5 or amide group, which can be converted by hydrogenolysis or a y 0 one to our on atoms, into the carbox l rou or the rou CONHA one of the residues R and R is H and the other is F, Hal, R or a g d f Fg 1 0 p 1 CR or SR R Z 10 R, and R being identical or different, represent alkyl of one is treated with agents giving off hydrogen or with catalytically to six carbon atoms, and activated hydrogen, or A is COOA,. j. a compound of Formula 1 l is reacted with a compound of For the preparation of the substituted 4-aminophenylacetic Formula 12; or a compound of Formula 13 is reacted with a acids and derivatives of Formula 1, as well as the salts thereof compound of Formula 14; with acids or bases and quaternary ammonium salts and opk. a compound of Formula 15 is reacted with a compound of Formula 16; or a compound of Formula 17 is reacted with a compound of Formula 18, optionally in the presence of a F riedel-Crafts catalyst:

l. a compound of Formula 19 is reacted with an amine of Formula 20, or an amine of Formula 21, 22 or 23 is reacted with a compound of Formula 24 or 25 under N-alkylation conditions, wherein the compounds 24 and 25, when reacted with a compound of Fonnula 2 l in accordance with the meanings indicated hereinabove for R and R can also represent a single compound.

wherein R in compound 19 preferably means an electron-attracting group, such as N CN,SO NR,R NR,COR or CF and both residues X of compounds 24 and 25, when reacted with the amine 2l, can also represent together an oxygen or sulfur atom;

m. an amino compound of Formula 21 is reacted with one or two identical or different straight-chain or branched olefins of two to seven carbon atoms or with a straight-chain or branched alkadiene of four to 14 carbon atoms, the chain of which can also be interrupted by an oxygen or sulfur atom; or amino compounds of Formula 22 or 23 are reacted with a straight-chain or branched olefin of two to seven carbon atoms, which olefin can also be connected with the residue R or R directly or by way of a hetero atom, such as O or S; or

n. a compound of Formula 26 l-I-Z, 26 is reacted with an amine of Formula 27 R,R NHal 27 particularly in the presence of Friedel-Crafts catalysts; or

o. the substituent R (or R is introduced into a compound of Formula 1 containing, instead of R hydrogen (or, if R is H and R and R simultaneously represent together a tetramethylene group optionally containing one to two double bonds, containing, in place of R hydrogen), as follows:

R, (or R respectively) represents chlorine, bromine or iodine, the substituent is introduced by means of halogenation, particularly by reaction with elemental halogen, preferably with the addition of catalysts, such as iron-lll-, aluminum-, antimony-Ill-halides, tin-IV-halides, with hypohalous acids, tert.-butyl hypohalogenites, halo-halide compounds, such as CII, ClBr, and Brl, SO -halogens, preferably with the addition of peracids, and N-halocarboxylic acid amides, as well as imides or R, (or R respectively) represents iodine, the substituent is introduced by means of iodization, particularly also by reaction of the 3- (or 6-) Hg acetate compound with iodine, or

R, (or R respectively) represents N0 the substituent is introduced by nitration, particularly by reaction with nitric oxide, nitronium salts, preferably with the addition of Friedel- Crafts catalysts,HNO optionally in a mixture with acetic acid, acetic anhydride, H pyrosulfuric acid, fuming sulfuric acid, H SeO HCIO with acyl nitrates, such as acetyl or benzoyl nitrate, with nitric acid esters, such as ethyl nitrate, with nitrosulfonic acid, nitrosylsulfuric acid, nitroguanidine, with metallic nitrates (such as Cu, Fe, Mn, Co or Ni nitrate) in a mixture with acetic anhydride or glacial acetic acid, or

R, (or R respectively) represents R SR SOR,,, 50 R or r m the substituent is introduced particularly by reaction with R,,X or olefins of up to four carbon atoms, or by reaction with R SX R SOX R SO X or R,R NX in the presence of Lewis acids, especially Friedel-Crafts catalysts, optionally under conditions where HX is split off, or

p. in a compound of Formula 1 wherein R represents NH the NH: group is exchanged, after being converted into a diazonium salt, against halogen, N0 CN, R 8, R 0 or OH, or

wherein R represents CONH the CONH group is converted into 21 CN group by agents splitting 05 water, such as, in particular, P 0 POCI PCl or SOCl or wherein R represents N0 or 10 or l0 is in place of R the N0 group is reduced to NH or the IO or 10 group is reduced to iodine, or

wherein, in place of R there is NH-NH or Nl-lNl-l substituted by hydrocarbon residues, this hydrazine group is replaced by bromine or iodine, or wherein R represents Hal, Hal is exchanged against NR,R or

wherein, in place of R there is one of the residues OM,, SM,, N(M,) or SO N(M )B2, this substituent taking the place of R is reacted with olefins of two to four carbon atoms, diazoalkanes of one to four carbon atoms or with compounds R X,, if desired under conditions wherein M,X is split off, or

wherein R represents NHR,, the NHR group is acylated to the NR,-COR group by treatment with ketenes of two to five carbon atoms, or with carboxylic acid derivatives suitable for acylating reactions, such as carboxylic acid esters, anhydrides, or halogenides derived from carboxylic acids of one to five carbon atoms, or this carbonamide group is hydrolytically liberated from one of the functional derivatives thereof, or

wherein R represents SR or NO is in place of R the SR group is oxidized to the SOR or SO R group, or the nitroso group is oxidized to the nitro group, or

wherein in place of R there is a sulfonic acid residue, particularly a sulfonic acid halogenide, a sulfonic acid ester or a sulfonic acid anhydride, this sulfonic acid derivative is reacted with an amine of F ormula 28 in a compound of Formula 1 (wherein R represents H and R and R represent simultaneously together a tetramethylene group optionally containing one to two double bonds) wherein, in place of R there are the substituents mentioned above for R these substituents are converted in an analogous manner, or

q. in a compound of Formula 1 wherein lOl040 (H4O two of the residues R R and R represent H and the third of these residues either represents H; or NH OH or SH stands in place thereof, the H atom standing in place of this third residue, or the groups standing in place of this third residue, are replaced, analogously to processes and (p), respectively, by one of the residues F, Hal, R,,,OR,, or SR or r. compounds of Formula 1 wherein R, and R,,, being identical or different, represent alkyl of one to seven carbon atoms substituted by OM, or SM,, and wherein one of the substituents OM, or SM, can also be replaced by X,, is reacted, under conditions splitting off H 0, H 8 or M,X,, to O-ring or S-ring containing compounds, or

s. compounds of Formula 29 A -COCOOH are decarbonylated, or t. compounds of Formula 30 R2 R3 R0 30 are treated with agents giving off hydrogen or with catalytically activated hydrogen, or with a compound of the Formula 14 (R M or u. a compound of Formula 1 wherein, in place of A, there is COOM,, COOR COO-acyl or CO-Hal is optionally reacted with a compound of Formula 3 l or with an olefin derived from 31 by formal H O splitting-off procedure or with an epoxide derived from 31 by a formal dehydrogenation, or with compounds of Formulas 32 to 36, or with an ethyleneimine derived from 33 by formal dehydrogenation, or with diazomethane, diazoethane, phenyldiazomethane, or hydroxylamine:

A,OH 31 A,OAcyl 32 A A NH 33 v. compounds of Formula 1 wherein in place ofA there is:

E E E QA iiNAzA: or HI'NAt are hydrolyzed to carboxylic acids, esters or amides of Formula 1, or

w, H O is chemically added to compounds of Formula 1 wherein CN is in place of A, with the formation of amides of Formula 1, or

x. compounds of Formula 37 (Z-COCH are subjected to a Willgerodt reaction in the presence of the amines 33 or 34, particularly with the addition of polysulfides, or

compounds of Fonnula 38 (Z CA, NOH) are subjected to a Beckmann rearrangement, particularly with the addition of acidic catalysts, or

compounds of Formula 39 (Z CO-A,) are subjected to a Schmidt degradation reaction with HN or y. an aldehyde of Formula 40 is reacted with nitrohydroxylamine acid or benzenesulfonyl hydroxylamine, particularly in an alkaline solution, or an aldoxime of an aldehyde of Formula 40 is oxidized, particularly with H 0 or peracids, to a hydroxaimic acid of Formula 1, or

2. compounds of Formula 1 wherein, in place of A, the group C( NR, -,)OR,,, is present, preferably in the form of a salt, are reacted to orthoesters of Formula 1 with alcohols of Formula 41; or compounds of Formula 42 are reacted with ortho-carbonic acid esters of Formula 43 to ortho-esters of Formula 1:

R OH 41 A,,-YA and A,,Y have the meaning of A,; and

A YA, has the meaning of A or 2b. a compound corresponding to Formula 1 except that, in place of at least one double bond of the benzene nucleus or (if R, and R together represent tetramethylene optionally containing one to two double bonds) of the naphthalene nucleus, a saturated C-C bond is present, is treated with dehydrogenating agents, such as, in particular, dehydrogena tion or metal oxide catalysts, chloranil, sulfur, selenium or alkyl disulfides; or

zc. a compound corresponding to Formula 1 except that, in place of R and R the residues H and R are present, is cyelized especially in the presence of acids and/or Lewis acids, such as Friedel-Crafts catalysts or optionally with agents splitting off water, such as P 0 POCl l 'Cl or COCI or optionally under other conditions splitting off HX HX or HHX or zd. from a compound corresponding to Formula 1 except that, in place of the residues R and R there is present a tetramethylene monosubstituted by X optionally containing a double bond, or disubstituted by X,,, the substituent or substituents X is or are eliminated as HX with the formation of one or two double bonds; or

ze. from a compound corresponding to Formula 1, except that, in place of the residues R and R there is present a tetramethylene disubstituted by X and X in the 1,2- or 1,4- or 3,4-position and optionally containing a double bond, the two substituents X and X, are eliminated respectively with the formation of a double bond, especially with metals, such as Zn, ZnCu, Na or Li, or with organometallic compounds, such as Grignard compounds or organolithium compounds; and/or zf. a compound of Formula 1 is optionally converted into the physiologically compatible salts thereof with acids or bases or quaternary ammonium salts and/or the derivatives thereof splittable under physiological conditions, particularly the anhydrides; or optionally racemate mixtures of Formula 1 are separated into the individual racemates, and any racemates of Formula 1 present are separated in a conventional manner into their optical antipodes; and/or the compounds of Formula 1 are liberated from their salts with acids or bases.

Suitable alkyl groups in the residues R, to R are: methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, furthermore sec.butyl and tert.butyl, R and R can represent together (CH Cl-l CH-(CH CH,-CH CPI-CH or -CH CH-CH CH. The residues R and R moreover represent individually preferably the following:

l-Pentyl, 2-pentyl, Z-methylbutyl, 3-methylbutyl, neopentyl, 3-pentyl, l-hexyl, 3-methylpentyl, 4-methylpentyl, 3,3- dimethylbutyl, 2,3-dimethylbutyl, heptyl, 4,4-dimethylpentyl, or together, in the form of alkylene residues, optionally in the form of alkylene residues interrupted by O or S, preferably propylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, 2-oxatetramethylene, 2-oxapentamethylene, 2-oxahexamethylene, 3 -oxapentamethylene, 3-oxahexamethylene, 3-oxaheptamethylene, 3- oxaoctamethylene, 4-oxaheptamethylene, 4-oxaoctamethylene, Z-thiatetramethylene, Z-thiapentamethylene, 2-

thiahexamethylene, 3-thiapentamethylene, 3-thiahexamethylene, 4-thiaheptamethylene, 4-thiaoctamethylene, 3- thiaheptamethylene, 3-thiaoctamethylene, l-methyltetramethylene Z-methyltetramethylene, l -ethyltetramethylene, Z-ethyltetramethylene, l -propyltetramethylene, 2-propyltetramethylene, l -isopropyltetramethylene, 2-isopropyltetramethylene, l-methylpentamethylene, Z-methylpentamethylene, 3-methylpentamethylene, l-ethylpentamethylene, Z-ethyIpentamethylene, 3-ethylpentamethylene, lisopropylpentamethylene, 2-isopropylpentamethylene, 3-isopropylpentamethylene, l-propylpentamethylene, 2-propylpentamethylene, 3-propylpentamethylene, l,2-dimethylpentamethylene, l,3-dimethylpentamethylene, l,4-dimethylpentamethylene, l,5-dimethylpentamethylene, l-methyl-2-ethyl-pentamethylene, l-methyl-3- ethylpentamethylene, 1-methyl-4-ethylpentamethylene, lmethyl-5-ethylpentamethylene, l,2-diethylpentamethylene, l ,3-diethylpentamethylene, l ,4-diethylpentamethylene, 1,5- diethylpentamethylene, 2,3-diethylpentamethylene, 2,4- dimethylpentamethylene, 3,B-diethylpentamethylene, lmethyl-3-oxapentamethylene, 2-methyl-3-oxapentamethylene, l ,2-dimethyl-3-oxapentamethylene, 2,4- dimethyl-3-oxapentamethylene, l ,5-dimethyl-3-oxapentamethylene, l-ethyl-3-oxapentamethylene, 2-ethyl-3-oxapentamethylene, l-ethyl-2-methyl-3-oxapentamethylene, 2-ethyl- 4-methyl-3-oxapentamethylene, l-ethyl-5-methyl-3-oxapentamethylene, l,2-diethyl-3-oxapentamethylene, 2,4-diethyl-3- oxapentamethylene, 2,5-diethyl3-oxapentamethylene, lisopropyl-3-oxapentamethylene, 2-isopropyl-3-oxapentamethylene, l-isopropyl-2-methyl-3-oxapentamethylene, 2- isopropyl-4-methyl-3-oxapentamethylene, l-isopropyl-S- methyl-3-oxapentam ethylene, l-methyl-3-thiapentamethylene, 2-methyl-3-thiapentamethylene, 1,2-dimethyl-3- thiapentamethylene, 2,4-dimethyl-3-thiapentamethylene, 1,5- dimethyl-3-thiapentamethylene, l-ethyl-3-thiapentamethylene, 2-ethyl-3-thiapentamethylene, l-ethyl-Z-methyl- 3-thiapentamethylene, 2-ethyl-4-methyl-3-thiapentamethylene, 1-ethyl-5-methyl-3-thiapentamethylene, 1,2- diethyl-3-thiapentamethylene, 2,4-diethyl-3-thiapentamethylene, l,5-diethyl-3-thiapentamethylene, l-isopropyl- 3-thiapentamethylene, 2-isopropyl-3-thiapentamethylene, lisopropyl-2-methyl3-thiapentamethylene, 2-isopropyl-4 methyl-3-thiapentamethylene or l-isopropyl-5-methyl-3- thiapentamethylene.

The residues A A and A represent preferably the followmg:

Hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-pentyl, isoamyl, n-hexyl, nheptyl, n-octyl, n-decyl, n-dodecyl, allyl, crotyl, hydroxymethyl, propargyl, 2-hydroxyethyl, Z-hydroxy-n-propyl, 3- hydroxy-n-propyl, 2-methoxyethyl, 2-ethoxyethyl, 3-oxa-5- hydroxypentyl, 3-oxa-5-methoxypentyl, 3-oxa-5-butoxypentyl, 3,6-dioxa-8-hydroxyoctyl, 3,6-dioxa-8-methoxyoctyl, 3-

oxa-S-ethoxypentyl, Z-aminoethyl, 3-aminopropyl, 2- dimethylaminoethyl, Z-diethylaminoethyl, 2-di-npropylaminoethyl, B-dimethylaminopropyl, 3- diethylaminopropyl, Z-methyl-3-diethylaminopropyl, cyclohexyl, cyclopentyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, N-methylpiperidyl-( 4), (N-methylpiperidyl-3 3)- methyl, 2-(N-methylpiperidyl-2)-ethyl, 2-piperidinoethyl, 2- pyrrolidinoethyl, 2-homopiperidinoethyl, 2-morpholinoethyl, 2-thiomorpholinoethyl, 2-(N-methylpiperazino)-ethyl, 2-(N- ethylpiperazino )-ethyl, 2-( N-phenylpiperazino)-ethyl, 2-( N-2- hydroxy-ethylpiperazino)-ethyl, 2-( N methylhomopiperazino)-ethyl, 3-piperidinopropyl, 3-pyr rolidinopropyl, 3-(N-methylpiperazino)-propyl, 3-(N-ethylpiperan'no )-propyl 3 N-phenylpiperazino )-propyl, 3 morpholino-propyl, 3-thiomorpholino-propyl, Z-morpholinopropyl, 2-piperidinopropyl, 2-pyrrolidino-propyl, 2-(N- methylpiperazino)-propyl, 2-methyl-3-morpholino-propyl, 2- methyl-3,-piperidino-propyl, 2-methyl-3-pyrrolidino-propyl, ldimethylaminobutyl, l-diethylaminobutyl, 2-mercaptoethyl, 2-methylmercaptoethyl, 2-ethylmercaptoethyl, 3-methylmercaptopropyl, 3-ethylmercaptopropyl, phenyl, benzyl, pethylphenyl, p-methylbenzyl, o-tolyl, p-tolyl. 2-phenylethyl, lnaphthyl, Z-naphthyl or l-phenylethyl.

ln CON/X --NA, represents preferably piperidino, pyrrolidino, morpholino, thiomorpholino, N-methylpiperazino, N-ethylpiperazino, N-propylpiperazino, N-phenylpiperazino, N-( 2 hydroxyethyl )-piperazino, piperazino, N-methylhomopiperazino or N-phenylhomopiperazino.

A, represents preferably ethylene, propylene, butylene, methylethylene, lmelhylpropylene, l-methylbutylene or pentylene.

N-alkyl in Y represents preferably methylamino, dimethylamino, ethylarnino, diethylamino, n-propylarnino, din-propylamino, isopropylamino, diisopropylamino, n-butylamino, n-propylmethylarnino, isobutylamino, see-butylamino, tert.-butylamino or methylethylamino.

ln C(OR. R represents preferably methyl, ethyl, npropyl and n-butyl.

The above-mentioned processes will now be described in greater detail:

a. The saponification of suitable functional acid derivatives of carboxylic acids of Formula 1 can be conducted, as set forth in greater detail in the literature, in a neutral, acidic or alkaline medium at temperatures between 20 and 300. Acids suitable for hydrolysis are, for example, especially hydrochloric, sulfuric, phosphoric and hydrobromic acid; suitable bases are sodium, potassium or calcium hydroxide, or sodium or potassium carbonate. Preferred solvents are water, ethanol, methanol, dioxane, tetrahydrofuran, dimethyl formamide or mixtures thereof, particularly the mixtures which contain water. However, it is also possible to saponify the acid derivatives to form aminophenylacetic acids of Formula 1, for example, in ether or benzene, with the addition of strong bases, such as potassium carbonate or without solvents by melting together with alkalis, such as potassium and/or sodium hydroxide or alkaline earths,

A particularly preferred embodiment of the invention is the saponification of corresponding thioamides, eg, the correspondingly substituted phenylthioacetomorpholides, piperidides,-pyrrolidides, -dimethylamides or -diethylamides. Such thioarnides are obtainable by reaction of the correspondingly substituted acetophenones with sulfur and the corresponding amine. Also the amides, obtainable by reacting the acetophenones with ammonium polysulfide in accordance with the method by Willgerodt known from the literature, are highly suitable as starting materials. The thioamides or amides are preferably hydrolyzed by heating with aqueous hydrocholoric acid. The thioamides or amides need not be necessarily isolated, in this connection; rather, it is also possible to subject the reaction mixture to hydrolysis in situ. By the dry heating of suitable esters of Formula 1, such as tertiary alkyl esters in particular, to temperatures between 50 and 350, the aminophenylacetic acids of Formula 1 are obtained. The thermolysis can also be conducted in inert solvents, such as benzene, water, dimethyl forrnamide, ethylene glycol, glycerin, dimethyl sulfoxide, cyclohexanol, preferably with the addition of catalytic amounts of acids, such as p-toluenesulfonic acid.

b. The oxidation of suitable preliminary products of Formula 2 containing a group oxidizable to a carboxyl group, to ob tain the aminophenylacetic acids of Formula 1 of this invention, can be conducted with various oxidation agents, as set forth in the literature, particularly with air or oxygen, preferably with the addition of catalysts, such as Mn, Co, Fe, Ag, V with silver oxide, preferably together with copper oxide; with H 0 preferably in the presence of alkalis; with organic peracids, such as peracetic acid, perbenzoic acid or perphthalic acid; with potassium permanganate in an aqueous or acetonic solution and/or in an acidic, neutral or alkaline reaction medium, optionally with the addition of MgSO with chromic acid or CrO preferably in glacial acetic acid, if desired, with the addition of benzene, or sulfonic acid; with nitrous acid; with preferably 2-68 percent nitric acid, if desired under pressure (up to 100 atmospheres); with nitrogen oxides or with sodium or potassium hydroxide/O in a melt; or with hypohalogenites. In these oxidation processes, the reaction is preferably conducted in inert solvents, such as water, glacial acetic acid, dioxane, benzene, acetone, tetrahydrofuran, dimethyl formamide, ethanol, methanol, or in the mixtures of these solvents with one another, and at temperatures between -30 and 300, suitably at room temperature.

c. m-Diazoacetophenones of Formula 3, obtained from the corresponding benzoic acids by way of the acid chlorides with diazoalkanes, can be rearranged into the compounds of Formula 1 in accordance with the method of Wolff, as described in grater detail in the literature, for example, by heating and/or exposure to light and/or in the presence of catalysts, such as copper, silver or silver oxide, as well as in the presence of a compound A,OH, an amine A A NH or A NH or hydroxylamine, wherein A to A have the above-indicated meanings, at temperatures of preferably between 0 and 120. In order to produce the free aminophenylacetic acids (1, A COOH), the reaction is suitably conducted in an alkaline solution with the addition of sodium thiosulfate, first at 40 60, and thereafter at 80 100. Advantageously, inert organic solvents are added to the reaction mixture, such as dioxane or tetrahydrofuran.

d. Organometallic compounds of Formula 4 are obtainable by metallizing correspondingly substituted benzyl halogenides, particularly with alkali or alkaline earth metals, preferably with lithium or magnesium, or with dialkylcadmium or dialkylzinc compounds. These compounds yield with solid CO in accordance with conventional methods described in the literature, the aminophenylacetic acids of Formula 1. The metallization, such as, for example, the Grignardation, is conducted in solvents, such as ether, tetrahydrofuran, dioxane, or mixtures thereof with aromatic hydrocarbons, such as benzene, at temperatures between preferably l0 and the boiling temperature of the solvents employed. Preferably, a large excess of a mixture of magnesium filings and magnesium powder is employed, and during the Grignardation, a vigorous stream of carbon dioxide is passed through the reaction mixture, in order to suppress an organometallic synthesis of the thus-formed Grignard compounds with still unreacted halogenide. In place of the Grignard compounds, it is also possible to employ other compounds, especially the organometallic compounds described in greater detail above, which are obtainable in an analogous manner.

e. m-Halogenoacetophenones of Formula 5, producible by halogenating the corresponding acetophenones, or from the w-diazoacetophenones of Formula 3 with hydrogen halide in ether, can be arranged into acids of Formula 1 in accordance with the method of Faworskij, described in the literature, for example, in boiling xylene in the presence of a strong base, such as sodium hydroxide, or by heating in an aqueous ethanolic silver nitrate solution.

f. Benzyl alcohols of Formula 6, producible by reducing the corresponding benzaldehydes or benzoic acids, can be carbonylated into aminophenylacetic acids of Formula 1, as

described in the literature, at high pressures of up to 400 atmospheres and at high temperatures of up to 300, preferably with the addition of heavy metal catalysts, such as nickel carbonyls or cobalt carbonyls or halogenides. It is also possible to employ the corresponding alcoholates, such as, in particular, alkali metal alcoholates (e.g., sodium ethoxide)or alkaline earth metal alcoholates (e.g., calcium alcoholate, and at lower pressures, without the addition of heavy metal catalysts.

Finally, it is possible to carbonylate alcohols, esterified alcohols or halogenides of Formulas 6 and 7, respectively, to form the compounds of Formula 1 of this invention, in accordance with the method by Koch-Haaf described in the literature; in this connection, a preferred source of carbon monoxide is a mixture of formic acid and mineral acids, particularly concentrated sulfuric acid, The reaction is conducted at 20 to suitably under cooling at 0 to 30. ln compounds of Formula 7, the respective substituent is exchanged for hydrogen, B becomes R and, by way of the carbonylation reaction, carboxylic acids of Formula 1 are produced.

g. Malonic acid derivatives of Formula 8, producible by thermal decomposition of correspondingly substituted phenyloxalacetic acid diethyl esters and subsequent partial or complete alkaline saponification, can be decarboxylated to the compounds of Formula 1 as described in the literature, for example, by dry heating, or by heating in solvents, such as water, ethanol, dioxane or xylene, to temperatures of between 50 and 250. Suitably, the heating is continued until the evolution of carbon dioxide has ceased.

h. Furthermore, substituted 4-aminophenylacetic acids of Formula 1 are obtainable by acid cleavage of a cor respondingly substituted a-acyl-phenylacetic acid derivative of Formula 9, as described in greater detail in the literature.

Ketoesters of Formula 9 can be prepared, for example, by condensing esters of acetic or benzoic acid with correspondingly substituted benzyl cyanides to form the a-acetylor oz-benzoyl-benzyl cyanides, subsequent conversion of the latter compounds with hydroxy compounds of the formula A OH wherein A, has the above indicated meanings (except for hydrogen), into the corresponding imido ether salts (e.g., hydrochlorides), and partial hydrolysis.

Acid cleavage of the keto derivatives of Formula 9 can be accomplished by treatment with a strong base, such as sodium, potassium or calcium hydroxide in solvents, such as water, methanol, ethanol, tetrahydrofuran, dioxane, benzene, ether, or mixtures thereof. The temperature range of the reaction is between -l0 and 200. If it is desired to obtain the free aminophenylacetic acids of Formula 1 (A COOl-l), then the reaction mixture is preferably heated for several hours to the boiling temperature of the solvent.

i. It is also possible to obtain a compound of Formula 1 by starting with a preliminary product containing, in addition or in place of hydrogen atoms, one or several groups substitutable by hydrogen and/or C N and/or C C double bonds and/or C E C triple bonds, and treating this preliminary product with agents evolving hydrogen. Groups substitutable by hydrogen are, inparticular: Hal; oxygen in an N-oxy, sulfinyl or carbonyl group; sulfur in a thiocarbonyl group; hydroxyl; mercapto; amino; hydroxyl, mercapto or amino substituted by a hydrocarbon residue; or diazonium salt groups.

Thus, it is possible to reduce, for example, a-hydroxy-, achloro-, a-bromo-, a-iodo-, a-mercapto-, a-amino-, abenzyloxy-, a-benzylamino-, a-oxoor a-thio-3,5-dimethyl-4- pipen'dino-phenylacetic acid, or the ethyl ester thereof, to 3,5- dimethyl4-piperidino-phenylacetic acid or the ethyl ester thereof; or a-hydroxy-, a-chloro-, a-bromo-, a-iodo-, a-mercapto-, a-amino-, a-benzyloxy-, a-benzylamino-, a-oxoor athio-3,6-dimethyl4-piperidino-phenylacetic acid to 3,6- dimethyl-4piperidino-phenylacetic acid. It is also possible to reduce 3-butyryl-, 3-thiobutyryl-, 3-(l-hydroxybutyl)-, 3-(1- aminobutyl)-, 3-( lchlorobutyl)-, 3-( l-bromobutyl)-, 3-( liodobutyl)-, 3-( l-benzyloxybutyl)-, 3-( l-benzylaminobutyl)-, 3-( l-mercaptobutyl)-, or 3-( l-benzylmercaptobutyl)-4-pyrrolidino-a-methyl-phenylacetic acid, or the 2- HHUM) l-U diethylaminoethyl esters thereof, to 3-n-butyl-4-pyrrolidino-amethyl-phenylacetic acid or the 2-diethylaminoethyl ester thereof, and to reduce 3-butyryl-, 3-thiobutyryl, 3-( l-hydroxybutyl)-, 3-( l-aminobutyl)-, 3-( l-chlorobutyl)-, 3 l bromobutyl)-, 3-(l-iodobutyl)-, 3-(l-benzyloxybutyl)-; 3-( lbenzylaminobutyl)-, 3-( l-mercapto-butyl)- or 3-( l-benzylmercaptobutyl)2-ethoxy-4-pyrrolidino-a-methyl-phenylacetic acid 2-diethylaminoethyl ester to the 2'-dlethylaminoethyl ester of 3-n-butyl-2-ethoxy-4-pyrrolidino-a-methyl-phenylacetic acid. Likewise it is possible to reduce 3-vinyl-a-ethyl-, 3-ethynyl-a-ethyl-, 3-ethyl-a-vinylor 3-ethyl-a-ethynyl-4- hornopiperidino-phenylacetic acid or the 2-piperidinoethyl esters thereof to 3,a-diethyl-4-homopiperidino-phenylacetic acid or the Z-piperidinoethyl ester thereof, or to reduce 3- vinyl-a-ethyl-, 3-ethynyl-a-ethyl-, 3-ethyl-a-vinylor 3-ethyla-ethynyl-4-homopiperidino-tS-isopropyl-mercapto-phenylacetic acid 2'-piperidinoethyl ester to the 2-piperidlnoethyl ester of 3,a-diethyl-4-homopiperidino -6-isopropyl-, mercapto-phenylacetic acid.

Furthermore, 4-(n-butylamino)-3-sulfamoyl-5-ethoxyphenylacetic acid or the isopropyl ester thereof can be alkylated, under hydrogenating conditions, with propionaldehyde, butyraldehyde, acetone, butanone-( 2) to obtain 4-(n-butylpropylamino)-, 4-(dibutylamino)-, 4-(n-butylisopropylamino)- or 4-(n-butyl-sec. butylamino)-3 sulfamoyle-S-ethoxy-phenylacetic acid or the isopropyl esters thereof. Also, sulfinyl compounds can be reduced to thioethers, such as, for example, 3-methyl-sulfinyl-, 3 methyl- 5-ethylsulfinyl-, 3-isopropyl-5-isopropyl-sulfinyl-, I i-methylsulfinyl-2-sec.butoxy-, 3-ethyl-sulfinyl-2-methylor 3- isopropyl-sulfinyI-6-methoxy-4-homopiperidinmphenylacetic acid N'-(2diethylamino-ethyl)-amide to the corresponding thioethers. Still further, it is possible, for example, to cleave hydrogenolytically the benzyl-, diphenylmethyl-, triphenylmethylor a-picolyl-esters of 3-trifluoromethyl-, 3-tert. butyl-, 3ethylmercapto-, 3-sulfamoyl-, 3-isopropoxyor 3-hydroxy-4- morpholino-a-ethyl-phenylacetic acid or -6,a-diethyl-phenylacetic acid or -a-ethyl-naphthyl-l-acetic acid to readily obtain the free carboxylic acids, or, for example, to remove the benzyl group in the benzyl amide of 4-piperidinonaphthylacetic acid under hydrogenating conditions.

The hydrogenation of unsaturated quaternary ammonium salts and N-oxides of Formula 10 is important. Thus 3-ethylsuli'onyh, 3methylsulfonyl-5 or -6-ethoxy-, 3-diethylsulfamoylor 3-trifluoro-methyl-5-methoxy-4-pyridinium-a-npropyl-phenylacetic acid bromide or the corresponding ethyl esters thereof, or 3-trifluoromethyl-4-pyridinium-a-n-propylnaphthyl-lacetic acid ethyl ester bromide, can be reduced to the d-piperidino derivatives thereof. Likewise, 3-nitro-5- or 6- ethoxyor 3-nitro-5- or -6-isopropyl-4-pyridiniuma-methylphenylacetic acid n-butyl ester chloride or 3-nitro-4-pyridinium-a-methyl-naphthyll -acetic acid nbutyl ester chloride can be hydrogenated to the 3-amino-4-piperidino compounds. Also, it is possible without difficulties to reduce, for example, 3,5- or 2,3-dimethyl-4-piperidino-a-methyl-phenylacetic acid N-oxide or 3-methyl-4-piperidino-a-methyl-naphthyl-l-acetic acid dodecyl ester N-oxide to form the Noxide-free derivatives.

Likewise of importance are the hydrogenation processes involving naphthalene or tetralone derivatives to the 5,6-, 6,7-, 7,8-dihydroand 5,6,7,8 -tetrahydronaphthalenes. Thus, 4- piper-idino-e-methyl-naphthyl-l-acetic acid and the ethyl ester of 2-ethoxy-4-pyrrolidino-5oxo-5,6,7,8- tetrahydronaphthyl-l-acetic acid can be hydrogenated to the corresponding 5,6,7,8-tetrahydronaphthlene derivatives, and 4 homopiperidino-naphthyll -acetic acid can be hydrogenated to the corresponding 5,6- or 6,7- or 7,8- dihydroor 5,6,7,8-tetrahydronaphthalene compound.

For catalytic hydrogenation and/or hydrogenolysis reactions suitable catalysts are, for example, noble metal, nickel and cobalt catalysts. The noble metal catalysts can be present on substrates (e.g., palladium on charcoal, calcium carbonate or strontium carbonate), in the form of oxide catalysts (e.g., platinum oxide), or finely distributed metallic catalysts.

Nickel and cobalt catalysts are suitably employed as Raney metals, nickel can also be utilized on kieselguhr or pumice as the support. The hydrogenation can be conducted at room temperature and normal pressure, or also at elevated temperatures and/or elevated pressures. Preferably, pressures of between 1 and 100 atmospheres and temperatures of between and 200, particularly between room temperature and +l00 are employed. The reaction is suitably conducted in the presence of a solvent, such as water, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, dioxane, acetic acid or tetrahydrofuran; it is also possible to employ mixtures of these solvents with one another. For purposes of hydrogenation, the free compounds or the corresponding salts thereof, e.g., the hydrochlorides or sodium salts, can be employed.

When hydrogenating unsaturated bonds and in the hydrogenolysis of benzyl groups, the process is preferably con ducted at normal pressure, in such a manner that the hydrogenation is interrupted after the stoichiometric quantity of hydrogen has been absorbed. Fundamentally, it is possible to operate in an acidic, neutral or basic range. For such commands which contain a C N double bond, a reaction in a neutral or basic medium is preferred.

Also generally applicable as a reduction method is the reaction with nascent hydrogen. The latter can be produced, for instance, by treating metals with acids or bases. Thus, it is possible to employ, for example, a mixture of zinc with acid or alkali solution; iron with hydrochloric acid or acetic acid; or tin with hydrochloric acid. Likewise suitable is sodium or another alkali metal in a lower alcohol, such as ethanol, isopropanol or butanol. Furthermore, it is possible to use an aluminum-nickel alloy in an alkaline-aqueous solution, optionally with the addition of ethanol. Also, sodium or aluminum amalgam in an aqueous-alcoholic or aqueous solution are suitable for the production of nascent hydrogen. The reaction can also be conducted in a heterogeneous phase; in this connection, an aqueous phase and a benzene or toluene phase are preferred. The reaction temperatures employed generally range between room temperature and the boiling point of the solvent used.

Still further suitable reducing agents are complex metal hydrides, such as, in particular, lithium aluminum hydride, and also sodium borohydride, in the presence of aluminum chloride or lithium bromide. The reaction conditions must be selected so that the group A (A having the previously indicated meanings) remains intact. Suitably, the reaction is conducted in an inert solvent, e.g., ether, tetrahydrofuran, ethylene glycol dimethyl ether. The, reaction is advantageously terminated by boiling the reaction mixture. The thus-formed metal complexes can be decomposed in a conventional manner, for example with an aqueous ammonium chloride solution.

Additional suitable reducing agents are, e.g., sodium dithionite in an alkaline or ammoniacal solution; iron(ll)- hydroxide; tin(ll)-chloride; hydrogen sulfide, metal hydrogen sulfides, sulfides and polysulfides; hydriodic acid or sodium sulfite.

It is also possible to reduce one or several carbonyl groups to CH groups in accordance with methods known from the literature, by Clemmensen or WollT-Kishner.

The Clemmensen reduction can be conducted, for example, by treating the carbonyl compounds with a mixture of zinc and hydrochloric acid, with amalgamated zinc and hydrochloric acid, or with tin and hydrochloric acid. The reaction is conducted either in an aqueous-alcoholic solution or in a heterogeneous phase with a mixture of water and benzene or toluene. The reaction is terminated by heating the reaction mixture to the boiling point of the solvent employed. The metal can either be provided first, and the acid added dropwise, or, conversely, the acid can be provided and the metal added in incremental portions.

The Woltf-Kishner reduction is conducted by treating the carbonyl compounds with anhydrous hydrazine in absolute ethanol in an autoclave or a bomb tube; the reaction temperatures being as high as 250". A preferred catalyst is sodium al coholate. The reduction can also be varied in accordance with the HuangsMinlon method, by employing hydrazine hydrate as the reducing agent, and conducting the reaction in a highboiling solvent miscible with water, such as, for example, diethylene glycol or triethylene glycol, as well as in the presence of an alkali, such as, for example, sodium hydroxide. The reaction mixture is normally boiled for about 34 hours. Thereafter, the water is distilled off, and the residue is heated for some time to temperatures of up to about 200, resulting in decomposition of the previously formed hydrazone, and the originally present carbonyl group is converted into a CH, group during this procedure.

it is further possible to replace Hal atoms, particularly aromatically bound Hal atoms, by hydrogen; this is done by converting the corresponding Hal compounds into the organometallic, e.g., Grignard, compounds associated therewith, and hydrolyzing the latter compounds with water or dilute acids.

Basically, all conventional reducing methods described in the literature can be employed, depending upon which of the above-mentioned starting materials is selected.

j. It is possible to form compounds of Formula 1 from organometallic compounds of Formula 1 I, particularly with alkyl halogenides, preferably iodides, bromides or chlorides, or with alkylsulfuric or alkylsulfonic acid esters of Formula 12, in inert solvents, such as benzene, xylene, dioxane or tetrahydrofuran. Preferably, Friedel-Crafts catalysts, such as AlCl FeCl or ZnCl are added to the reaction mixtures. These organometallic compounds are especially alkali, alkaline earth, Zn or Cd compounds, or the alkaline earth-, Znor Cd-Hal compounds obtained by direct metallization, such as, for example, with butyllithium, phenyllithium, sodium hydride, sodium amide or metallic sodium or magnesium, of the corresponding hydrogen or halogen compounds.

On the other hand, compounds of Formula 13, particularly the correspondingly substituted a-chloro-, a-bromoor aiodo-phenylacetic acid derivatives, or the a-hydroxy-phenylacetic acid derivitives esterified with sulfuric acid or sulfonic acid derivatives, can be alkylated under quite analogous conditions, with metallic compounds of Formula l4, particularly alkali metal derivatives, such as butyllithium or methylsodium, or Grignard compounds, such as n-propyl-magnesium chloride.

k. Compounds of Formula 1 can also be obtained by reacting the halogen compounds of Formula 15 with preferably Grignard or organolithium compounds of Formula 16 derived from correspondingly substituted haloacetic acid derivatives. Advantageously, the bromoor iodoacetic acid derivatives are employed. The reaction is conducted in inert solvents, such as ether, tetrahydrofuran or dioxane, at temperatures between and 180 Under the same conditions, it is likewise possible to react phenyllithium or Grignard compounds of Formula 17 with substituted haloacetic acid derivatives of Formula 18, preferably with the bromoacetic or iodoacetic acid derivatives, in order to obtain the compounds of Formula 1.

Furthermore, it is possible to react compounds of Formula 17 wherein Q represents hydrogen with compounds of Formula 18, preferably with correspondingly substituted a-iodo-, abromo-, a-chloro-, a-hydroxyor a-acyloxyacetic acid derivatives, under the conditions of a Friedel-Crafts alkylation, to obtain the compounds of Formula 1. Examples for catalysts suitable in this connection are Lewis acids, such as AlCl;,, SbCl, FeCl BF ZnCl; or mineral acids, e.g., HF, H 80 H PO.,, or the anhydrides thereof, such as P 0 Preferably, the reaction is conducted in inert solvents, such as carbon disulfide, hexane or nitrobenzene, and at temperatures between 0 and 200". in general, the methods are employed which are set forth in the literature. 1. The reaction of amines of Formula 20 with compounds of Formula 19, or the reaction of amines of Formula 21, 22 or 23 with alkyl compounds of Formula 24 or 25, respectively, is conducted basically in accordance with the interchange reactions which are conventional and described in the literature. If, as the reaction component, a halogenide of Formula 19, 24 or 25 is selected, the reaction can be conducted in the presence or absence of a solvent. Examples of solvents are lower aliphatic alcohols, benzene or toluene. Depending upon which halogenide is employed as the starting material, the reaction is conducted at low temperatures, e.g., room temperature, or at elevated temperatures up to the boiling temperature of the solvent employed. In individual cases, it may be necessary to conduct the reaction under pressure or at elevated temperatures. The utilization of a catalyst, e.g., a base, is possible, but normally unnecessary. Advantageously, the amines are employed in excess.

If a phenol of Formula l9 (X, or an alcohol of the Formula 24 (X, OH), or a preferably lower aliphatic carboxylic acid ester of such a phenol or alcohol is employed as the starting substance, then the reaction with the amines is suitably carried out in the presence of a catalyst. A suitable catalyst is either a dehydrating or a dehydrogenating agent, or a mixture of these catalysts. An example of a dehydrating catalyst is aluminum oxide optionally activated with still other suitable oxides. As the dehydrogenation agents, there can be employed, for example, Raney nickel or the conventional noble metal catalysts, such as, e.g., palladium oxide or palladium charcoal.

As the starting material for this reaction, it is also possible to employ a compound of Formula 19 or 24 or 25 wherein X, represents a secondary or tertiary amino group. Under the reaction conditions of a so-called transamination, such a secondary or tertiary amino group in compounds of Formula 19 is exchanged, by treatment with amines of Formula 20, by the group R-,R,,N.

In a completely analogous manner, it is possible to exchange, by means of a transamination reaction, a secondary or tertiary amino group in compounds of Formula 24 or 25, reaction with amines of Formula 21 or 22 or 23, against the group NHZ, or NR Z, or NR,,Z,, respectively.

The reaction conditions for such a transamination are described in the literature. Advantageously, the amines of Formula 19 or 24 or 25 are employed in an excess, and the reaction is conducted in the presence of catalysts, such as acids, metallic salts, iodine, dehydration agents, hydrogenation-dehydrogenation catalysts, or sodium hydrogen sulfide. However, in isolated cases, such transaminations also take place in the absence of a catalyst. it is suitable to conduct the reactions in the presence of an inert solvent, and it is furthermore advantageous to operate under an elevated pressure as well as at elevated temperatures.

Furthermore, it is possible to reductively alkylate the amines 22 or 23 with aldehydes or ketones of one to seven carbon atoms; in this connection, these aldehydes or ketones can also be bound to the R, or R residues of the amines 22 or 23, respectively, either directly or by way of a hetero-atom, such as O or S. Aldehyde-ammonia compounds are produced as the intermediates in each case, i.e., compounds carrying a hydroxy group in the a-position with respect to the nitrogen, the hydroxy group is then removed by hydrogenolysis in accordance with the reducing methods explained in paragraph Preferably, the reductive alkylating processes are conducted in the presence of a suitable catalyst, examples of such catalysts being the conventional types, such as noble metal, Raney nickel or Raney cobalt. These catalysts can be present, for example, in the form of oxide catalysts, supported catalysts, or of finely divided metal catalysts. Suitably, the reaction is conducted under an elevated hydrogen pressure, as well as at elevated temperatures (up to about 250).

Such a reductive alkylation can also be carried out with chemical reducing agents, such as, for example, with formic acid, forrnamide or ammonium formiate, in accordance with the method of Leuckart-Wallach, as described in detail in the literature.

Preferred compounds of Formula 19 in this connection are p-iodo-, p-bromoor p-chlorophenylacetic acid derivatives. By the effect of groups strongly attracting electrons, such as, for example, N0 CN, SO NH acylamino or CF,, the Hal atom is losened in the 3-position and/or, if applicable, in the 2-, 5- or 6-position which facilitates the reaction with the secondary amines of Formula 20.

The reaction is conducted, depending upon the reactivity of the p-halophenylacetic acid derivatives, preferably between room temperature and 320, optionally in an autoclave under pressure (up to 200 atmospheres). It is possible, in this connection, to employ the amines of Formula 20 to be reacted in each particular case, such as piperidine, morpholine or pyrrolidine, in a large excess to simultaneously function as the solvent. Otherwise, the reaction is preferably conducted in inert solvents, such as chloroform, benzene, dioxane, tetrahydrofuran, dimethyl formamide, dichlorobenzene or ethylene glycol, using acid-binding additives, such as sodium or potassium carbonate.

Thus, it is simple to produce, for example, form 3nitro-, 3- cyano-, 3-methylsulfonylor 3-sulfamoyl-4-bromo-a-methylphenylacetic acid or the N-( 2-piperidinoethyl)-amides thereof, or from 3-nitro-, 3-cyano-, 3-methylsulfonyior 3- sulfamoyl-4-bromo-6-methylmercapto-a-methyl-phenylacetic acid, or from 3-nitro-, 3-cyano-, 3-methylsulfonylor 3- sulfamoyl-4-bromo-a-methyl-naphthyl-l-acetic acid, by reaction with piperidine, homopiperidine, thiomorpholine or pyrrolidine, the corresponding 4-piperidino-, 4-homopiperidino-, 4-thiomorpholinoor 4-pyrrolidino-phenylacetic acid derivatives or the -naphthyll-acetic acid derivatives.

When reacting primary amines of Formula 21 with compounds of Formula 24 or 25, respectively, the latter and former can also be present as one compound (due to the definition of the residues R and R for example, unmdihalogenoalkanes, such as 1,4-dibromobutane, 1,5- dichloropentane, l,6-diiodohexane, 2,2'-dichloroethyl ether, or 3,3'-dibromo-di-n-propyl sulfide; and especially sulfuror oxygen-ring compounds, such as tetrahydrofuran, -pyran, thiophene or -thiopyran. The reaction of such sulfuror oxygen-ring compounds of amines of Formula 21 is generally conducted under severe conditions, preferably at tempera tures above 150 in an autoclave.

m. It is likewise possible to alkylate the primary amines of Formula 21 or the secondary amines of Formula 22 or 23, respectively, to the compounds of Formula I, with olefines of two to seven carbon atoms. If the alkylation of compounds of Formula 21 is involved, two identical or two different olefins as the alkenyls can also be connected to form alkadienes, such as pentadiene-l,4, or, by way of an oxygen or sulfur atom, to di-unsaturated ethers or thioethers, such as divinyl sulfide or divinyl ether. When alkylating secondary amines of Formula 22 or 23 with an olefin, this alkenyl can also be connected with one of the residues R or R either directly or by way of an oxygen or sulfur atom.

Such addition reactions of olefins to primary or secondary amines are described in the literature. Suitably, the reaction is conducted at an elevated pressure (up to about 300 atmospheres) and at an elevated temperature (up to about 350), It is advisable to add a catalyst during this reaction, such as, for example, a cobalt or molybdenum catalyst, or an alkali metal, such as sodium, for example. In these reactions, it is advantageous to employ the amines of Formula 21, 22 or 23 in excess.

n. The reaction of a compound of Formula 26 with a haloamine of Formula 27 is conducted under the conditions of a Friedel-Crafts alkylation of aromatics as described in greater detail in paragraph (k) and in the literature. Thus, it is possibie, for example, to react 3,a-dimethyl-phenylacetic acid or 3,:x-dimethyl-naphthyl-l-acetic acid or 2,3,a-trimethyl-phenylacetic acid, or the diethylamides thereof, with N- chloropiperidine in nitrobenzene or carbon disulfide in the presence of AlCl BF or ZnCl to 3,a-dimethyl-4- piperidino-phenylacetic acid or to 3,a-dimethyl-4-piperidinonaphthyl-l-acetic acid or 2,3,a-trimethyl-4-piperidino-phenylacetic acid, or the diethylamides thereof.

0. In compounds of Formula I wherein hydrogen is, in place of the residue R or, if R H, and R. and R simultaneously represent together a tetramethylene group optionally containing one to two double bonds, and hydrogen is in place of R the following substituents can be directly introduced in the 3- position (or the 2-position, respectively):

a. Chlorine,

by direct reaction with elemental chlorine in an inert solvent, such as water, tetrachloromethane, acetic acid, without or with the addition of specific catalysts, such as, for example, F eCl AlCl SbCl or SnC1 preferably between l0 and 100 (as described in the literature); or

by reaction in a strongly hydrochloric acid solution with H 0 or with NaClO 3, wherein the chlorination is effected by nascent chlorine (as described in the literature); or

by reaction with SO CI in an inert solvent, such as chlorobenzene, in the presence of radical-forming catalysts, e.g., peroxides, at preferably -l80 (as described in literature); or

by reaction with NO Cl or NOCl in carbon disulfide or hexane.

,B. Bromine,

readily by direct reaction with elemental bromine in an inert solvent, such as, eg, carbon disulfide, acetic acid or tetrachloromethane, especially with the addition of specific catalysts effective as bromine transfer agents, such as, e.g., iron filings, A101,, AlBr FeCl iodine or pyridine, preferably between 30 and (as described in the literature); or

by reaction with hypobromous acid, acyl hypobromites, N- bromoimides, such as N-bromosuccinimide, N-bromophthalimide or other bromine-yielding agents, such as 1,3-clibromo- 5,5-dimethyl-hydantoin, in inert solvents, such as nitrobenzene or carbon disulfide, preferably at l0 to (as described in the literature); or

by reaction with NOBr or NO Br in carbon disulfide or cyclohexane.

'y. Iodine,

by direct reaction with elemental iodine, particularly in the presence of HgO in an inert solvent, such as alcohol, acetic acid or benzene, preferably at temperatures between 0 and 1 20 (as described in the literature); or

by reaction with iodine-alkali iodide solutions, in the presence of carbonates, acetates, alkali metal hydroxide solutions, ammonia or amines (as described in the literature); or

by reaction of mixtures of alkali metal iodides and oxidation agents, such as alkali metal iodates, alkali metal nitrates or H 0 in inert solvents, such as water, acetic acid or ethanol, wherein the reaction is conducted with nascent iodine; or

by reaction with Cl] in dilute acetic acid, preferably at 50lO0bL (as described in the literature); or

after mercuration, for example, in an aqueous or acetic medium with mercury (ll )-acetate to form the 3-Hg-O- COCl-i compound and exchange of the organometallic residue against iodine, e.g., by reaction with iodine or iodinealkali hydroxide solutions (as described in the literature).

a. Nitro,

by nitration methods as described in detail in the literature.

The actual nitrating reactant is the nitronium ion N05 consequently all nitronium salts, or reaction mixtures wherein this nitronium ion is potentially present, can be employed for the nitration of the aromatic nucleus. For example, there can be used a mixture of anhydrous nitric acid with BF metallic nitrates such as Cu-, Fe-, Mn-, Co or Ni-nitrate, in a mixture with acetic acid or acetic anhydride; metallic nitrates, such as Ag-, Ba-, Na-, K-, HN,- or Pb-nitrate, in a mixture with Friedel-Crafts catalysts, such as Alcl FeCl BF or SiCl,; alkyl nitrates, such as ethyl nitrate, in a mixture with concentrated sulfuric acid, HBF, or Lewis acids, such as RG1 SnCl,,, PCl Alcl SiCh, SbCl or FeCl nitryl fluoride, chloride, bromide, perchlorate or tetrafluoroborate, preferably in the presence of Freidel-Crafts catalysts, such as AlCl FeCl ZrCL, or AlBr in solvents, such as carbon disulfide, n-pentane or CHCI nitric oxides, such as N 0 N 0,, or N 0 in the presence of concentrated H 80 HF or Friedel-Crafts catalysts, such as F AlC1 or FeCl optionally in solvents, such as tetramethylene-sulfone or acetic acid, Suitable solvents for these nitration reactions are, e.g., nitromethane, nitroethane, nitropropane or acetonitrile. The reaction is preferably conducted between 20 and +120.

In addition, the following agents are generally usable for introducing the nitro group into the aromatic nucleus: concentrated nitric acid; mixtures of concentrated sulfuric acid with concentrated or anhydrous nitric acid; alkali nitrates, such as sodium or potassium nitrate, in a mixture with concentrated sulfuric acid; mixtures of concentrated nitric acid with pyrosulfuric acid, fuming sulfuric acid, acetic acid, or acetic anhydride; mixtures of nitric acid, sulfuric acid and acetic acid; acetyl or benzoyl nitrate; nitrosulfonic acid, producible by introducing S into fuming HNO nitrosylsulfuric acid, nitroguanidine; highly concentrated nitric acid in the presence of dehydrating agents, such as P 0, or anhydrous hydrofluoric acid, optionally in solvents, such as nitrobenzene or polychloroethanes.

A special nitration reaction comprises dissolving the substance to be nitrated in a solvent such as HCl CH C1 or CCl,,, introducing concentrated sulfuric acid under the level of the reaction solution, and then adding anhydrous nitric acid in CHCl CH Cl or CCl Generally, the reaction is conducted between 20 and 150.

5. Alkyl, alkylmercapto, alkylsulfinyl, alkylsulfonyl, amino, alkylamino or dialkylamino.

by reacting with the corresponding chlorine, bromine, iodine, hydroxy or acyloxy compounds, such as, e.g., ethyl iodide, n-propyl bromide, n-butanol, ethyl acetate, isopropyl sulfur chloride, isobutyl sulfinyl bromide, sec.butyl sulfochloride, hydroxylamine, chloramine or diethyl chloramine, in accordance with the conditions of a Friedel-Crafts reaction, as described in greater detail in the literature. Suitable catalysts are Lewis acids, such as AlCl AlBr SnCl,,, ZnCl FeCl SbCl or HF, and suitable solvents are n-hexane, carbon disulfide, nitrobenzene, tetramethylenesulfone or nitroethane. Preferably, the reaction is conducted between 70 and 180".

In place of alkyl derivatives, the corresponding olefins can also be reacted according to Friedel-Crafts, as set forth in the literature,

Thus, it is possible, for example, to alkylate 4-piperidino-a methyl-phenylacetic acid or 4-piperidino-a-methyl-naphthyL l-acetic acid or 4-piperidino-6-ethyl-a-methyl-phenylacetic acetic acid or the di-n-butylamides thereof, with isobutylene, methyl iodide, n-propanol or isopropyl acetate, in accordance with Friedel-Crafts, to obtain the 3-alkyl-4-piperidino-amethyl-phenylacetic acids or the 3-alkyl-4-piperidino-amethyl-naphthyl-l-acetic acids or the 3-alkyl-4-piperidino-6- ethyl-a-methyl-phenylacetic acids or the di-n-butylamides thereof. Analogously, it is possible to obtain, from 4-pyrrolidino-phenylacetic acid, 4-pyrrolidino-naphthyl-l-acetic acid or 4-pyrrolidino-6chloro-phenylacetic acid or the piperidides thereof, and isopropyl sulfur bromide, ethylsulfinyl chloride, n-butyl sulfochloride, hydroxylamine or N,N- dimethyl-hydroxylamine, the 3-isopropylmercapto-, 3-ethylsulfinyl-, 3-n-butylsulfonyl-, 3-aminoand 3-dimethyl-amino- 4-pyrrolidino-phenylacetic acid or naphthyl-l-acetic acid or 6-chlorophenylacetic acid, or the piperidides thereof. Additionally, the corresponding compounds substituted in the 2- position are produced from the naphthyH-acetic acid derivatxves.

p. After diazotization of compounds of Formula I wherein the residue R represents NR the diazonium group can be exchanged for F, Cl, Br, 1, N0 CN, alkylmercapto, alkoxy or OH.

The exchange against fluorine is described in the literature. The diazotization is conducted, for instance, in anhydrous hydrofluoric acid, and the reaction mixture is then heated, or the poorly soluble diazonium tetrafluoroborates, produced in substance, are thermally decomposed, whereby the 3-fluorocompounds are produced.

Chlorine is preferably exchanged against the diazonium chloride group in an aqueous solution in the presence of CuCl in accordance with the method of Sandmeyer (as described in the literature).

The bromine exchange can be conducted, for example, according to the methods described in the literature. The diazonium bromide can either be decomposed to the bromine compounds in an aqueous solution in the presence of CuBr in accordance with Sandmeyer or by reaction with bromine to form the diazonium perbromide and subsequent boiling in solvents, such as water or lower alcohols. However, it is also possible to convert the diazonium bromides, with HgBr into the diazonium mercury bromides, and to decompose the latter thermally to the desired bromo-compounds.

The exchange of the diazonium iodide group against iodine is achieved by just gentle heating. Catalysts, such as Cul, CuBr or CuCl can also be added in order to accelerate the reaction (as described in the literature).

The diazonium group can be exchanged for cyanogen, for example, by following the Sandmeyer method in the presence of CuCN and alkali cyanides, such as NaCN or KCN, already under cold conditions, preferably at 0-50, or, in accordance with the variation by Gattermann, with alkali cyanide with the addition of powdered copper, It is also possible to employ a double salt of KCN and nickel cyanide as the catalyst. The preferred pH ranges for the cyanogen exchange range between 4 and 9 (as described in the literature).

The exchange of the diazonium group, preferably the diazonium tetrafluoroborate or diazonium cobalt(lIl)-nitrite, against the nitro group is described in the literature and can be accomplished, for instance, by reaction with alkali nitrites, such as NaNO or KNO in the presence of catalysts, such as copper oxide or copper hydroxide, even under cold conditions.

Furthermore, the diazonium salt group can be exchanged against alkoxyor alkylmercapto groups as described in the literature. For example, the diazonium group is replaced by heating in an aqueous-alcoholic solution by the corresponding alkoxy groups. The exchange against alkylmercapto groups is conducted by reaction with alkyl mercaptans, preferably in an alkaline solution, by heating or even under cold conditions, with the addition of catalysts, such as powdered copper. The diazosulfides, which are fonned as intermediates, need not be isolated.

By heating, if necessary by boiling, it is also possible to hydrolyze the aqueous solutions of the diazonium salts to the corresponding phenols (as described in the literature).

Compounds of Formula 1 carrying, in place of R a carbonamide group can be converted into the corresponding nitriles by splitting off water. This is done, for example, thermally, preferably between 170 and 300, especially with the addition of catalysts, such as A1 0 pumice, powdered glass, sand, or graphite, or chemically with dehydrating agents, such as, for instance, P 0 P 8 PCl, POCl PCl together with chlorine, SO Cl AlCl as a double salt with NaCl, BF, (mostly with the addition of an organic acid), COCl (with the addition of tertiary amines, such as pyridine, or acylated secondary amines), the trichloromethyl ester of chloroformic acid, benzotrichloride with the addition of catalysts, such as ZnCl FeCl AlCl concentrated sulfuric acid or phosphoric acid), acid anhydrides (e.g., acetylbenzoic acid), aromatic sulfonic acids or sulfonic acid halogenides (such as p-toluenesulfochloride). The reaction is conducted either with or without the addition of inert solvents, such as benzene, dichlorobenzene, tetrahydrofuran, xylene, or nitrobenzene, preferably between and 250.

A nitro group present in the 3-position of the compounds of Formula 1 can be converted into the NH group in accordance with the reducing method set forth in paragraph (i). Likewise, it is possible to reduce 3-iodoxy-or 3-iodoso-derivatives to 3- iodo compounds of Formula 1, particularly with hydrogen iodide, optionally with the addition of red phosphorusv Also, the 3-iodoso compounds can be disproportioned to the 3- iodoxyand the 3-iodocompounds. The iodoso group can be directly introduced into the 3-position, for example, by reaction with (IO) SO, (as described in the literature).

Furthermore, diazotization can be conducted on compounds of Formula 1 carrying, in place of R a hydrazino group, or a hydrazino group substituted by hydrocarbon residues. After conversion into the diazonium perbromides or iodides, with bromide or iodine, respectively, preferably in solvents such as methanol, ethanol or acetic acid, a thermolysis reaction at preferably 50180 results in the 3-bromoand 3-iodocompounds, respectively, of Formula 1.

Compounds of Formula 1 carrying in the 3-position an OH, SH, Nl-l or SO NH group, optionally also present as the salts, particularly alkali or alkaline earth salts, are mono-(or optionally dialkylated), for example, by reaction with olefins, such as isobutylene, alkyl halogenides, such as ethyl iodide, npropyl bromide, isopropyl chloride, or with equivalent alkyl derivatives, such as, e.g., alkylsulfuric acid esters or alkylsulfonic acid esters, e.g., dimethyl sulfate or isopropyl-ptoluenesulfonic acid esters, and also with aliphatic diazo compounds, such as diazomethane, with nitrogen being split off, also, as the occasion permits, with amines or alcohols. Suitable solvents are, for instance, water, methanol, ethanol, benzene, tetrahydrofuran, xylene, or mixtures thereof. In many cases, alkalis, such as NaOH or KOH are added in equivalent amounts or in an excess. Most frequently, the reaction is conducted under the alkylating conditions described in paragraphs l and (m).

Thus, it is possible to produce from 3-hydroxy-, 3-mercapto-, 3-aminoor3-sulfamoyl-4 homomorpholino-phenylacetic acid or 6-n-butyl-phenylacetic acid, or naphthyl-l-acetic acid, or the esters of diethyLamides thereof, by reaction with methyl iodide, the 3-methoxy-, 3-methylmercapto-, 3- methylaminoand 3 -dimethylaminoor the 3-methylsulfamoyland 3dimethylsulfamoyl-4-homomorpholinophenylacetic acids or 6-n-butyl-phenylacetic acids or naphthyll acetic acids, or the esters or diethylamides thereof. Furthermore, from B-mercaptoor 3-hydroxy-4-di-nbutylamino-2,a-dimethyl-phenylacetic acid heptyl ester or from the 2'-morpholinoethyl ester of 3-mercapto-, 3-hydroxy-, 3- bromo-S-mercaptoor 3bromo-S-hydroxy-4-di-n-butylamino-a-methyl-phenylacetic acid, or from the heptyl ester of S-mercaptoor 3-hydroxy-4-piperidino-naphthyl-l-acetic acid, the corresponding 3-(or 5-, respectively)methylmercaptoand 3-(or 5-, respectively)methoxy-derivatives can be obtained by reaction with diazomethane or dimethyl sulfate.

Compounds of Formula l with an amino group or with a monoalkylamino group in the 3-position can be acylated with carboxylic acids or carboxylic acid derivatives, as described in the literature. Examples of carboxylic acid derivatives are carboxylic acid esters, anhydrides or halogenides, such as chlorides, bromides or iodides, and also amides. The carboxylic acid derivatives themselves can be employed as the solvent, or the reaction can be optionally conducted, for instance, in benzene, toluene, dioxane, tetrahydrofuran or chloroform. When acylating with carboxylic acid halogenides, a base is preferably added, such as sodium or potassium carbonate, pyridine, dimethylamine or trimethylamine. However, it is also possible to acylate with ketenes in inert solvents. Also, thioamides, iminoethers, amidoximes, amidines or hydrazidines can be converted into the amides, for example, by heating with water or aqueous solvents (as described in the literature).

The oxidation of compounds of Formula 1 containing an alkyl-mercapto group in the 3-position to obtain the corresponding sulfinyl or sulfonyl compounds is accomplished by oxidation methods as described in paragraph (b) and in the literature. In particular, the following oxidation agents are em ployed: H preferably in the presence of alkalis; organic peracids, such as peracetic acid, perbenzoic acid, mchloroperbenzoic acid, or perphthalic acid; potassium permanganate in an aqueous or acetone solution and/or in an acidic, neutral or alkaline reaction medium, optionally with the addition of MgSO chromium trioxide, preferably in acetic acid (optionally with the addition of benzene) or sulfuric acid; nitric acid, optionally under pressure (up to atmospheres nitric oxides; nitrogen peroxide; chlorine or bromine (elemental or in the form of hypohalogenites); iodosobenzene. It is also possible to oxidize electrolytically.

ln these oxidation reactions, inert solvents are preferably employed, such as water, acetic acid, dioxane, acetone, tetrahydrofuran, methanol, ethanol, dimethyl formamide, benzene, or mixtures of these solvents, and the processes are conducted at temperatures between 30 and 200, preferably at room temperature.

For oxidizing corresponding 3-nitroso-compounds to the 3- nitro-compounds of Formula I, there are predominantly employed strong nitric acid or mixtures of HNO and H 0 in acetic acid (as described in the literature).

Finally, it is possible to obtain the 3-sulfamoyl compounds of Formula 1 from correspondingly substituted reactive 3-sulfonic acid derivatives, such as sulfonic acid chlorides, bromides, iodides, anhydrides or esters, by reaction with ammonia, primary or secondary amines, as described in the literature. Preferably, the reaction is conducted in inert solvents, such as benzene, toluene, tetrahydrofuran, chloroform or dioxane, at temperatures between 20 and ln the reaction of the sulfonic acid halogenides, bases are preferably added, such as K CO pyridine or dimethyl aniline. Also, the sulfonamides are obtainable from the corresponding sulfonic acid ammonium salts at temperatures between and 400, by reduction of sulfonic acid azides, e.g., with zinc dust in acetic acid. Finally, it is possible to convert sulfinic acids with hydroxylamine or with amines, with the addition of halogens, such as chlorine or bromine, or sulfenamides by KMnO, oxidation, into sulfonamides (as described in the literature).

In those compounds of Formula 1 wherein R H and R, and R together represent a tetramethylene group containing optionally one to two, preferably two, double bonds, especially a 2-substituted naphthyl-l-acetic acid derivative unsubstituted in the 3-position, an NH CONH N0 10, I0 NHNH the latter optionally substituted by hydrocarbon residues, Hal, OM,, SM N(M,) SO N(M,) NHR,, SR or NO group in the 2-position or a sulfonic acid residue present in the 2-position, can be converted into another of the aforementioned substituents, by analogous methods described in paragraph (p) above.

q. ln compounds of Formula 1 wherein two of the residues R R and R represent hydrogen and the third of these residues either also represents hydrogen or one of the residues NH OH or SH, it is possible to introduce into the 2-, 5- or 6 position, fluorine, chlorine, bromine, iodine, alkyl, alkoxy or alkylmercapto, analogously to the processes set forth in paragraphs (0) and/or (p), wherein the introduction of these residues into the 3-position is described.

Additionally, a diazonium salt group in the 2, 5- or 6-posi tion can be substituted reductively by hydrogen, optionally with the addition of metallic catalysts, such as copper or copper oxide. Preferred hydrogen donors, in this connection, are alcohols, if desired in the presence of zinc, ether, hypophosphorous acid, sodium stannite, an alkaline formaldehyde solution, or formic acid derivatives. Also, it is possible, for example, to reduce the diazonium tetrafluoroborates with complex metal hydrides, such as sodium borohydride, in a suspension or in a solution (as described in the literature).

r. The cyclization of substituted 4-aminophenylacetic acid derivatives of Formula 1 (wherein, in place of the residues R and R there are OH- or SH-substituted alkyl groups of one to seven carbon atoms) to O-ringor S-ring-containing compounds is conducted analogously to the methods conventional for the production of cyclic ethers of the morpholine type, or cyclic thioethers of the thiomorpholine type. Diols or dithiols can preferably be converted into the desired cyclic ethers or thioethers by heating with acidic catalysts. Catalysts predominantly employed in this connection are: hydrogen chloride (e.g., concentrated aqueous hydrochloric acid), hydrogen bromide, phosphoric acid, sulfuric acid (concentration between about 50 and 98 percent), sulfonic acids, such as ptoluenesulfonic acid, acidic ion exchangers, Lewis acids, such as zinc chloride, and acid anhydrides, such as acetic anhydride. The above-mentioned acids can be employed in the anhydrous or aqueous phase. If desired, an additional inert solvent is employed, such as benzene, toluene or xylene. The reaction temperatures of the diol or dithiol cyclization are in the range of about 50-200, depending upon the cyclization agent employed; the reaction times are between about 8 and 120 hours. Particularly preferred is the ring closure with 48 percent hydrobromic acid at about 130.

The oxygen-containing or sulfur-containing rings can also be closed by heating of a salt, e.g., the hydrochloride, of a diol or dithiol, to about 2002l0, or by splitting off H O or H S from the free diol or dithiol on SiO /Al- O at about 375400.

In place of the diols or dithiols, it is also possible to react, for example, the corresponding dihalogenides, such as the dichlorides, dibromides or diiodides to the desired or S- ring-containing compounds, with metallic oxides, such as Na O, K 0, MgO or CaO, or with metallic sulfides, such as Na S, K or BaS, in inert solvents, such as dichlorobenzene, ethylene glycol, dimethyl formamide or xylene at 60250.

Starting compounds of Formula 1 wherein one of the residues R and R is substituted by OH or SH, and the other residue R or R is in each case substituted by X,, preferably chlorine, bromine or iodine, are cyclized in accordance with the methods of the Williamson synthesis, wherein suitably the OH or SH group is converted into the corresponding alkali alcoholate or alkali mercaptide. The latter or former compound readily splits off alkali halogenide, thereby forming the desired 0- or S-ring. Thus, it is readily possible to react 3-chloro-4-bis- (Z-hydroxyethyl )-aminoor 3chloro-4-bis-( 2-chloroethyl amino-phenylacetic acid; or 3-chloro-4-bis-( 2-hydroxylethyl )-aminoor 3-chloro-4-bis-( 2-chloroethyl )-aminonaphthyl-l-acetic acid; or 3-chloro-4-bis-(2-hydroxyethyl)- aminoor 3-chloro-4-bis-(2-chloroethyl)amino-6-isopropylphenylacetic acid; or the cycloheptyl esters thereof to form 3- chloro-4-morpholino-phenylacetic acid; or 3-chloro-4- morpholino-naphthyl- 1 acetic acid; or 3-chloro-4- morpholino-6-isopropyl-phenylacetic acid; or the cycloheptyl esters thereof. Furthermore, it is possible to obtain 3-ethylmercapto-4-thiomorpholino-wmethyl-phenylacetic acid or the 2'-ethoxyethyl ester of 2ethylmercapto-3-bromo-4- thi0morpholino-oz-methylphenylacetic acid from 3-ethylmercapto-4-bis( 2-mercaptoethyl)-aminoor from 3-ethylmercapto-4-bis-( 2-bromoethyl )amino-a-methyl-phenylacetic acid, 2ethylmercapto-3-bromo-4-bis-( 2-mercaptoethyl)-aminoor from the 2'-ethoxyethyl ester of 2-ethylmercapto-3-bromo-4- bis-( 2-bromoethyl)-amino-a-methylphenylacetic acid.

Still further, correspondingly substituted sulfur-ring-containing compounds wherein the sulfur is present as a sulfinyl or sulfonyl group can be reduced to the desired S-ring-containing compounds of Formula I in accordance with the methods indicated in paragraph (i).

s. it is possible to obtain compounds of Formula 1 from correspondingly substituted arylpyruvic acids by decarbonylation. This can be done thermally in an analogous manner to the decarboxylation of malonic acids, as described in para graph (g), or chemically, for example, by heating in concentrated sulfuric acid, or by oxidative decarbonylation in a sulfuric acid or hydrochloric solution in the presence of oxidation agents, such as H 0 Thus, for example, the methyl ester of 3-nitro-4-piperidinocinnamic acid or the methyl ester of 3-nitro-4-pyrrolidino-6- chloro-cinnamic acid can be brominated in CS to form the dibromocinnamic acid derivative, then reacted with piperidine in alcohol, and hydrolyzed with dilute sulfuric acid to 3-nitro-4piperidino-phenylpyruvic acid or 3-nitro-4-pyrrolidino-o-chloro-phenylpyruvic acid, which latter acids are then oxidatively decarbonylated in a hydrochloric acid solution with H 0 to 3-nitro-4-piperidino-phenylacetic acid or 3- nitro-4-pyrrolidino--chloro-phenylacetic acid. Analogously, 4-piperidino-naphthyl-l-acetic acid is obtained from 3-(4- piperidino-naphthyl-l )-acrylic acid by way of the dibromide thereof and 4-piperidino-naphthyl-l-pyruvic acid.

t. Compounds of Formula 1 are obtained by hydrogenating quinone methides of Formula 30, producible by splitting off H O or hydrogen halide from compounds of Formula l wherein OH or halogen is in place of R,, with the aid of, e.g., polyphosphoric acid, concentrated H SO A1 0,, or NaOH or KOH, in accordance with the hydrogenation methods described in paragraph (i).

Thus, for example, the quinone methides of Formula 30, obtained from the n-butyl esters of 3,5,a-trimethyl-4- homopiperidino-a-hydroxy-phenylacetic acid or of 3,0:- dimethyl4-homopiperidino-6-methoxy-a-hydroxy-phenylacetic acid by splitting off H O, can be hydrogenated to the n-butyl esters of 3,5,atrimethyl-4-homopiperidino-phenylacetic acid or of 3,a-dimethyl-4-homopiperidino-6-methoxy-phenylacetic acid.

Furthermore, in order to form the compounds of Formula 1 of this invention, organometallic compounds of Formula 14, such as, for example, n butyllithium or methyl magnesium iodide, can be chemically added to quinone methides of Formula 30. The reaction is preferably conducted in inert solvents, such as ether, tetrahydrofuran, benzene, toluene, dichloroethane, and at reaction temperatures between 20 and the boiling temperatures of the solvents. in case of organometallic compounds unstable in air, the reaction is conducted in an inert gas atmosphere, such as nitrogen.

Thus, it is possible, for example, to chemically add methyl, ethyl or isopropyl magnesium iodide to the quinone methides of Fonnula 30 obtained by splitting off HCI from 3- trifluoromethyl-4-morpholino-a-chloro-phenylacetic acid diethylamide or 2-trifluoromethyl-4-morpholinoa-chloronaphthyl-l-acetic acid diethylamide or 2,a-dichloro-4- morpholino-6-methyl-phenylacetic acid diethylamide, to obtain the corresponding a-methyl-, a-ethylor a-isopropylphenylacetic acid derivatives.

u. Esters or ester amides of Formula 1 are obtained by reacting carboxylic acids of Formula 1 (A COOH), under conditions wherein water is split off, with alcohols of Formula 31 or with amines of Formula 33 or 34.

Thus, the esters are produced in accordance with conventional methods as described in the literature. For example, the respective carboxylic acids can be esterified with alcohols of Formula 31 with or without the addition of catalysts, such as sulfuric acid, hydrogen chloride, phosphoric acid, aromatic sulfonic acids, such as p-toluenesulfonic acid, or with the addition of acidic ion exchange resins and the like, preferably between 10 and the boiling temperature of the respective alcohol, the latter being usually employed in excess. In order to shift the esterification equilibrium, it is possible to operate in the presence of water-binding agents, such as, for example, with molecular sieves or anhydrous heavy metal sulfates, such as copper, iron, nickel, cobalt or zinc sulfate. Also, the water or reaction can be removed by azeotropic distillation, with hydrocarbons, such as benzene or toluene, or chlorinated hydrocarbons, such as chloroform or l,2-dichloroethane, being the entraining agent.

The esterification and amidation reactions can take place under very gentle conditions if the water of reaction is chemically neutralized by the addition of preferably equimolar quantities of carbodiimides, such as N,N'dicyclohexyl carbodiimide, in inert solvents, e.g., ether, dioxane, benzene or ethylene glycol dimethyl ether, particularly in the presence of bases, such as pyridine. Thus, for example, the corresponding esters or amides of Formula 1 can be obtained from 3-bromo- 4-piperidino-a-methyl-phenylacetic acid, 3-chloro-4- piperidino-a-methyl-phenylacetic acid, 3-chloro-4-piperidino- 5methyl-a-ethyl-phenylacetic acid, 3-chloro-4-piperidino-aethyl-naphthyl-l-acetic acid or 3-chloro-4-piperidino-6- bromo-a-ethyl-phenylacetic acid, respectively, by reaction with 3-oxa-5-methoxypentanol, Z-arninoethanol, cyclohexlOlO40 0H9 anol, or with Z-phenylethylamine, homopiperidine or 3-(N- ethyl-piperazino)PROPYLAMINE) Further, the carboxylic acids of Formula 1 (A COOH) can also be esterified to obtain the esters of Formula 1 of this invention with any desired esters of Formula 32, preferably employed in excess, especially in the presence of basic or acidic catalysts, such as, e.g., sodium alcoholate or sulfuric acid, in accordance with the interesterification methods described in the literature. Thus, it is possible, for example, to prepare the corresponding cyclopentyl, 2-cyclohexylethy1 or 4-thiaoctyl esters by reacting 3-bromo-4-piperidino-phenylacetic acid, 3-nitro-4-homomorpho1ino-a-methyl-phenylacetic acid, 2-nitro-4-homomorpholino-a-methyl-naphthyll-acetic acid and 2-iodo-3-nitro-4-homomorpholino-amethyl-phenylacetic acid, respectively, with cyclopentyl acetate, 2-cyclohexylethyl propionate or 4-thiaoctyl benzoate.

Esters of Formula 1 are also obtained by reacting the respective carboxylic acids with diazoalkanes, such as diazomethane, diazoethane or phenyldiazomethane, in inert solvents, such as ether, benzene or methanol, with nitrogen being split off (as described in the literature); or by chemically adding the carboxylic acids to olefins derived by formal H O splitting from alcohols of Formula 31, such as isobutylene or cyclohexene, or to acetylenes. As set forth in the literature, the addition reaction is preferably accomplished in the presence of catalysts, such as ZnCl BF concentrated sulfuric acid, arylsulfonic acids, pyrophosphoric acid, boric acid or oxalic acid, at O-200 and in inert solvents, such as dioxane, tetrahydrofuran, ether, benzene, toluene or xylene, Pressures between 1 and 300 atmospheres are employed. Thus, it is possible for example, to react 3-bromo-4-(2,6-dimethylpiperidino)-phenylacetic acid, 3-bromo-4-piperidino-amethyl-phenylacetic acid, 3-bromo-4-piperidino-naphthyl-l acetic or 3,6dibromo-4-(2,6-dimethylpiperidino)-phenylacetic acid with diazomethane, diazoethane or phenyldiazomethane to obtain the corresponding methyl, ethyl or benzyl esters, and to add same to 3-bromo-4-piperidino-amethyl-phenylacetic acid, 3,5a-trimethyl-4-piperidino-phen ylacetic acid, 3,a-dimethyl-4-piperidino-naphthyl-l-acetic acid or 2,3,a-trimethyl-4-diethylamino-phenylacetic acid, 5,8- dioxa-decenel 4-ethyl-4-aza-hexene- 1 5-isopropyl-4-oxaheptene-l, to obtain the corresponding 5,8-dioxadecyl-, 4- ethyl4-azahexyland 5-isopropyl-4-oxaheptyl esters.

The 2-hydroxyethylor 2-aminoethyl esters are obtained by adding the respective carboxylic acids to epoxides or to ethylene-imines, the aforementioned being producible from the alcohols 31 or from the amines 33 by dehydrogenation.

Whereas the reaction with epoxides is preferably accomplished in the presence of basic catalysts, such as sodium acetate, and at temperatures of up to 120, the ethyleneimines react in inert solvents at temperatures between and 30 with the carboxylic acids to form the amides of Formula 1. Thus, for example, it is readily possible to react 3,5-dibr0mo- 4-piper-idino-a-methyl-phenylacetic acid, 2-bromo-4- piperidino-naphthyl-l-acetic acid, 2,3-dichloro-4-piperidinoa-methyl-phenylacetic acid or 2bromo-3-cyano-4-di-npropylamino-a-isobutyl-phenylacetic acid with ethyleneimine, propyleneimine, ethylene oxide or propylene oxide to obtain the corresponding Z-hydroxyethylor 2 hydroxypropylarylacetic acid amides or esters.

The aminoarylacetic acid amides of Formula 1 can also be obtained by boiling carboxylic acids of Formula l (A COOH) with isocyanates of Formula 35 in an inert solvent, such as benzene, toluene or xylene, until the evolution of C0 has ceased. Thus, the corresponding arylacetic acid amides can be produced, for example, from 3-ch1or0-4- thiomorpholino-a, a-dimethyl-phenyl or -naphthyl-1 acetic acid by reaction with methyl, ethyl, n-octyl or n-dodecyl isocyanate.

As described in the literature, it is also possible to employ, in place of the isocyanates, the readily accessible azides A CON since these azides are converted, under the reaction conditions, into the isocyanates of Formula 35. Furthermore,

esters of Formula 1 of this invention are obtained by reacting metallic salts of Formula 1 wherein A represents COOmetal, with compounds of Formula 36, in accordance with the methods described in the literature. Preferably, the silver or lead salts are employed, which are in most cases of low solubility; however, it is also possible to utilize the alkali or alkaline earth metal salts. The salts are preferably reacted in an inert solvent, such as ether, benzene or petroleum ether, with the compounds of Formula 36, such as, for example,, n-butyl bromide or n-dodecyl iodide, which are preferably employed in excess. Thus, for example, the corresponding arylacetic acid esters are obtained from the silver salts of 3,5-dinitro-4- homothiomorpholino-phenylacetic acid, 3-nitro-4-piperidino- -chlorophenylacetic acid, or 4-piperidino-5,6,7,8- tetrahydro-naphthyl-l-acetic acid by reaction with butyl bromide, 2-ethyl-3-oxa-hexyl iodide or 2-isopropyl-2-aza-pentyl bromide,

Furthermore, compounds of Formula 1 are obtained by reacting esters of Formula 1 (A COOR preferably in the presence of basic catalysts, with alcohols of Formula 3 i, esters of Formula 32, amines of Formulas 33 and 34, respectively, or with hydroxylamine.

The reaction of the esters of Formula 1 (A C ORH) with alcohols of Formula 31 or esters of Formula 32 takes place in accordance with the interesterification methods described in the literature and is preferably conducted in the presence of basic catalysts, such as sodium methylate or ethylate, in particular so that, after the equilibrium has been established, one reactant is withdrawn from the equilibrium by distillation. Thus, it is possible, for example, to interesterify the methyl ester of 3-ethylmercapto-4-piperidino-a-ethyl-phenylacetic acid, the ethyl ester of 4-piperidino-5,8-dihydro-a-methylnaphthyl-l-acetic acid or the methyl ester of 3-ethylmercapto- 4-piperidin0-6-chloro-a-ethyl-phenylacetic acid to the corresponding n-hexyl esters with n-hexanol, or with n-hexyl acetate.

Amides or hydroxamic acids of Formula 1 are obtained likewise by reacting the esters of formula 1 (A COOR with amines of Formulas 33 and 34, respectively, or with hydroxylamine. Preferably, readily saponifiable esters are employed, such as methyl or phenyl esters, and the reaction is optionally conducted with the addition of a basic catalyst, such as sodium methylate or ethylate, in suitable solvents, such as water, methanol, benzene or chloroform, the temperature ranging preferably between 20 C and the boiling temperature of the solvent. Thus, it is ossible, for example, to react the methyl ester of 3-chloro-4-piperidino-a-methyl-phenylacetic acid, the methyl ester of 3-bromo-4-morpholino-5,6- dihydronaphthyl-l -acetic acid and the ethyl ester of 3-methylmercapto-4-piperidino--bromo-phenylacetic acid with hydroxylamine to the corresponding arylacetohydroxamic acid derivatives or, with N'-2-aminoethyl-N-methylpiperazine or with N-(2-aminopropyl)-piperidine or with morpholine to the corresponding arylacetic acid amides.

Furthermore, compounds of Formula 1 are obtained by reacting acid halides or acid anhydrides of Formula 1 (A COHal or COO-acyl) with alcohols of Formula 3 l, with amines of Formulas 33 and 34, respectively, or with hydroxylamine.

Thus, analogous to the methods described in the literature, the acid halogenides or the salts thereof (if amino-acid halogenides are involved), or the acid anhydrides can be reacted with the alcohols of Formula 31 with or without the addition of acid-neutralizing agents, such as, e.g., sodium or potassium hydroxide, sodium or potassium carbonate or pyridine, wherein preferably an excess of the alcohol is employed as the solvent.

The reaction with amines of Formulas 33 and 34, respectively, or with hydroxylamine is conducted as described in the literature. In this connection, the acidneutralizing agent preferably employed is an excess of the amine, and the inert solvents particularly utilized are ether, benzene, tetrahydrofuran, dioxane, methanol, or toluene.

Thus, it is possible, for example, to react 3-bromo-4- piperidino-a-methyl-phenylacetic acid or 4-homopiperidino- 2,3-di-methyl-a,a-di-n-butyl-phenylacetic acid chloride or anhydride with isopropanol or N-methyl-piperazine or with hydroxylamine to obtain the corresponding phenylacetic acid isopropyl ester or N-methyl-piperazide, or to obtain the corresponding phenylacetohydroxamic acid.

In all of these reactions of paragraph (u), the following alcohols A,OH of Formula 31 or the amines A A Nl-l of Formula 33 or the isocyanates A N C O of Formula 35 or the compounds A,X of Formula 36 are preferably employed: methyl-, ethyl-, n-propyl-, isopropyl-, n-butyl, isobutyl-, sec.- butyl-, tert.-butyl-, n-pentyl-, isoamyl-, n-hexyl-, n-heptyl-, noctyI-, n-decyl-, n-dodecyl-, allyl-, crotyl-, propargyl-, 2- hydroxyethyl-, 2-hydroxypropyl-, 3-hydroxypropyl-, 2- methoxyethyl-, 2-ethoxyethyl-, 3-oxa-5-hydroxy-pentyl-, 3- oxa--methoxy-pentyl-, 3-oxa-5-butoxy-pentyl-, 3,6-dioxa-8- hydroxy-octyl-, 3,6-dioxa-8-ethoxy-octyl-, 3,6-dioxa-8- methoxy-octyl-, 3-oxa-5-ethoxypentyl-, 2-aminoethyl-, 3- aminopropyl-, 2-dimethylaminoethyl-, 2-diethylaminoethyl-, 2-di-n-propyl-aminoethyl-, 3-dimetylaminopropyl-, 3- diethylaminopropyl-, 2-methyl-3-diethylamino-propyl-, cyclohexyl-, cycl0pentyl-, 2-cyclohexylethyl-, 3cyclohexylpropyl-, N-methylpiperidyl-4-, N-methyl-piperidyl-3-methyl-, 2-(N-methyl-piperidyl-2)-ethyl-, 2-piperidinoethyl-, 2-pyrrolidinoethyl-, 2homopiperidino-ethyl-, 2morpholinoethyl-, 2- thiomorpholino-ethyl-, 2(N-methylpiperazino)-ethyl-, 2(N- ethylpiperazino)-ethyl, 2-(N-phenylpiperazino)-ethyl-, Z-(N- 2-hydroxyethylpiperazino)-ethyl-, 2-( N-methylhomopiperazino)-ethyl-, 3-piperidino-propyl-,3-pyrrolidinopropyl-, 3-(N-methylpiperazino)-propyl-, 3-(N-ethylpiperazino)-propyl-, 3-(N-phenylpiperazine)-propyl-, 3- m0rpholin0pr0pyl-, 3-thiomorpholinopropyl-, 2-morpholinopropyl-, 2-piperidinopropyl-, Z-pyrrolidinopropyl-Z-(N- methylpiperazino)-propyl-, Z-methyl-3-morpholinopropyl-, 2- methyl-3-piperidinopropyl-, Z-methyl-3-pyrrolidinopropyl-, 4- dimethylaminobutyl-, 4-diethylaminobutyl-, 2-mercaptoethylphenyl-, benzyl-, o-tolyl', m-tolyl-, p-tolyl-, p-ethylphenyl-, pmethylbenzyl-, 2-phenylethyl-, l-naphthyl-, 2-naphthyl, lphenylethyl-alcohol or -amine or -isocyanate or -chloride, bromide, -iodide or -p-toluenesulfonate.

Esters of Formula 32 are preferably the esterification products of the above alcohols of Formula 31 with formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid or benzoic acid.

Preferred amines A,NH of Formula 34 are piperidine, pyrrolidine, morpholine, thiomorpholine, N-methylpiperazine, N- ethyl-piperazine, N-n-propylpiperazine, N-phenylpiperazine, N-( 2-hydroxy-ethyl)-piperazine, piperazine, N-methylhomopiperazine, or N-phenyl-homopiperazine.

Among the esters of Formula 1 (A COOA those of particular interest are readily cleaved physiologically. In this connection, particularly preferred are the vinyl, tert.-butyl, tetrahydro-Z-furtyl and tetrahydro-Z-pyranyl esters obtainable, for example, by reacting the free carboxylic acids with acetylene, isobutylene, 2,3-dihydrofuran and 2,3- dihydropyran, particularly with the addition of catalysts, such as ZnCl BF H 80 arylsulfonic acids, pyrophosphoric acid, boric acid or oxalic acid at Ol20 in inert solvents, such as dioxane, tetrahydrofuran, ether, benzene or xylene.

v. Compounds of Formula 1 can also be obtained by hydrolyzing derivatives of Formula 1 (carrying, in place of A, corresponding thioester, iminoether, oximinoether, hydrazone ether, thioamide, amidine, amidoxime or amide hydrazone groups) with dilute aqueous bases or acids, such as, e.g., ammonia, NaOH, KOl-I, Na CO K CO l-lCl, H 80 if desired with the addition of a solubilizer, such as ethanol or methanol, to the corresponding esters or amides, with hydrogen sulfide, ammonia or amines, hydrazine or hydrazine derivatives or hydroxylamine being split off. Whereas, for example, most of the iminoether hydrochlorides are immediately decomposed in an aqueous solution at room temperature into the esters and ammonium chlorides, other derivatives, such as, for example,

some amidoximes or thioamides, require temperatures of up to 100 for purposes of hydrolysis.

Thus, it is possible to hydrolyze, for example, 3-bromo-4- piperidino-a-methylor 3-bromo-4-piperidino-5-chloro-aethylor 2-bromo-3-nitro-4-piperidino-ethyl-phenylacetic acid iminoethyl ester HCl or -oximinoethyl ester HCl or hydra-zoniminoethyl ester HCl to the corresponding phenylacetic acid ethyl esters; and 3-nitro-4-piperidino-6-chlorophenylacetic acid thioarnide, amidoxime or amide hydrazone to the corresponding phenylacetamides.

w. Amides of Formula 1 are obtained by partially saponifying nitriles of Formula 1 (A CN) in alkaline or acidic media in accordance with methods known from the literature, for example, with an aqueous solution of sodium hydroxide or with concentrated sulfuric acid, at between -20 and 200, preferably between 0 and 100.

However, it is also possible to hydrolyze the nitriles to the amides of Formula 1 of the present invention by means of hydrogen peroxide or organic peracids, preferably in aqueousalcoholic or aqueous-acetonic NaOH, between 20 and 100.

Thus, the corresponding phenylacetamides of Formula 1 are produced from 3-chloro-4-piperidinoor 3-n-butyl-4- homopiperidino-6-ethoxy-benzyl cyanide. From 4-piperidinonaphthyll -acetonitrile, 4-piperidino-naphthyll -acetamide is produced.

x. The Willgerodt reaction, by means of which amides of Formula 1 are obtained from ketones of Formula 37, and which is described in the literature, also takes place by way of the hydrolysis of thioamides. The ketones 37 are reacted to the thioamides with sulfur and amines of Formula 33 or 34, optionally in inert solvents, such as, eg, dioxane or tetrahydrofuran, by boiling the reaction mixture for a longer period of time. The hydrolysis of the thioamides, which need not be isolated, is conducted under such gentle conditions that the saponification is arrested at the amide stage.

Thus, for example, there are obtained from 3,6-dichloro-4- dimethylaminoacetophenone, by reaction with Nl-l /S, 3,6- dichloro-4-dimethylaminophenyl-acetamide; from 3-fluoro-4- piperidino-acetophenone, 3-fluoro-4-piperidinophenyl-acetamide; from 3-fluoro-4-piperidino-l-acetonaphthone, 3-fluoro- 4-piperidinonaphthyll -acetamide.

The amides of Formula 1 are also obtained by subjecting oximes of Formula 38, as described in greater detail in the literature, to a Beckmann rearrangement process, preferably at temperatures between and 180, with acidic agents, such as, for example, concentrated sulfuric acid, phosphorus pentachloride or benzenesulfochloride. Thus, it is possible to rearrange, for example, [4-(2,6-diethylpiperidino)-3,6- diisopropoxy-a-methyl-benzyl]-n-propyl ketone oxime to the corresponding phenylacetic acid n-propylamide derivative. Likewise, from 4-piperidino-naphthyl-l-acetoxime, 4- pipen'dino-naphthyl-l-acetic acid N-methylamide is obtained.

Finally, ketones of Formula 39 are converted, by the Schmidt degradation of amides of Formula 1, in accordance with the description in the literature, with HN preferably in inert solvents, such as benzene or chloroform, and in the presence of acidic catalysts, such as concentrated sulfuric acid, for example, at temperatures between 40 and Thus, it is possible, for instance, to react 2-methyl-3-chloro-4- piperidino-benzylethyl ketone with HN to obtain 2-methyl-3- chloro-4-piperidino-phenylacetic acid N-ethylamide; from 4- piperidino-naphthyl-lmethyl)-ethyl ketone, 4-piperidinonaphthyll -acetic acid n-ethylamide is obtained.

y. Hydroxamic acids of Formula 1 are also obtained by reacting aldehydes of Formula 40 in accordance with the method by Angeli disclosed in the literature either with a salt, preferably an alkali or alkaline earth salt, of nitrohydroxylamine acid, for example, in an aqueous or alcoholic solution, or with benzenesulfonyl hydroxylamine, particularly in an alkaline-aqueous or alcoholic solution. In both cases, the salts are obtained from which the free hydroxamic acids are obtainable by acidification.

IOltlJtl (I151 crystalline copper sulphate, 40 parts diethanolamine, 50 parts ammonia (d 0.88) at 95 100 C. within hours. The dyestuff is isolated from the coppering solution by the addition of salt and careful acidification.

The coppered amino-disazo dyestuff is then acylated in an aqueous solution at pH 6 7 and a temperature of 20 30 C. with 20 parts 2,4,6-trifluoro-S-chloropyrimidine, the pH value being kept within the stated range by the addition of sodium carbonate. When the acylation is completed, the dyestuff is isolated with sodium chloride and dried at 35 C. ln the form of the free sulphonic acid the dyestuff corresponds to the formula COUPLING COMPONENT Z-amino-5-hydroxynaphthalene-l ,7-disulphonic amino-8hydroxynaphthalene-3 ,o-disulphonic acid.

The resultant dyestuffs have a blue color.

acid 2- EXAMPLE 296 0. l Mole 4-ureido-2-amino l -hydroxybenzene-5-sulphonic acid is diazotized and coupled soda-alkaline with 0.1 mole lamino-8-hydroxynaphthalene-2,4-disulphonic acid. The coupling solution is adjusted to a content of 2 moles/liter with caustic soda and then boiled under reflux for 3 hours to hydrolyze the ureido group. After cooling, the mixture is neutralized with hydrochloric acid. The dyestutf is metallized by the addition of 25 parts copper sulphate and 100 parts of a 2N sodium hydroxide solution at 45 C. and a pH value of 4 6 and, after 30 minutes, acylated at pH 6 7 and temperatures of 20 30 C. with 0.1 mole 2,4,6-trifluoro-5- chloropyrimidine. The resultant dyestuff of the formula is salted out. A blue dyeing is obtained on cotton.

EXAMPLE 297 A neutral paste of copper-phthalocyanine 3,3',3"- trisulphonic acid chloride, prepared from 600 g of technical 96 percent copper-phthalocyanine, is stirred with a little water. adjusted to 4 liters and reacted at a pH of 3.5 60.0 with 2l6 g N-methyl-N-(4-amino-2'-sulphobenzyl)-amine,

initially at 0 3 C. and finally at 20 35 C., with the addition of 300 ml (=295 g) pyridine, and the pyridine is subsequently distilled off from the resultant solution of copperphthalocyanine-disulphonic acid-monosulphonic acid-(3- sulpho-4'-methyl-aminomethyl-anilide) at pH 9.0 with steam. The solution is brought to 20 30 C and 300 g 2,4,6- trifluoro-S-chloro-pyrimidine are added dropwise in portions in the course of l to 2 hours, while maintaining a pH of6 '7 by the addition of a dilute sodium hydroxide solution. At the same time, the reaction mixture is diluted with water, as required, to such an extent that the dyestufi always remains dissolved.

There are obtained 10 liters of dyestuff solution which is separated from the excess acylating agent, adjusted to pH 7.0 by the addition of acetic acid and reprecipitated by adding 2.5 liters of a concentrated sodium chloride solution with stirring.

After filtering off with suction and drying at 30 C, there is obtained a clear turquoise-blue dyestufi' which is fixed on cotton from a soda-alkaline solution at 40 60 C. with a very good yield and fastness to washing.

If the NiPc-3,3',3"-trisulphonic acid chloride is used as starting material, then a turquoise blue is obtained which is only slightly more greenish and has equally valuable properties.

EXAMPLE 298 0. l Mole of the aminoazo dyestufi ofthe formula S 03H S 03H prepared according to the instructions of German Patent specification No. 1,115,865 (application F 27466 IVb/22 a) by coupling the diazonium compound from 2- aminonaphthalene-4,8-disulphonic acid with laminonaphthalene-o-sulphonic acid, further diazotizing the resultant aminoazo dyestuff, coupling with the equivalent amount of 2,S-diaminonapthalone-4,8-disulphonic acid and conversion into the aminotriazole are dissolved in 1,000 parts by volume of water at pH 6 and mixed at a temperature of 20 30 C, while stirring, with 21 parts 2,4,6-trifluoro-5- chloropyrimidine. The hydrofluoric acid which is slowly liberated is neutralized by means of a sodium carbonate solution until the reaction is completed. The dyestuff is subsequently separated by the addition of sodium chloride, isolated and dried at about 50 C. in a vacuum. it is a yellow powder which dissolves in water to give a yellow color.

EXAMPLE 299 38.9 Parts of the dyestuff obtained by soda-alkaline coupling from 6 nitro-2-diazo-1-hydroxybenzene-4-sulphonic acid and 2-hydroxynaphthalene are stirred in 200 parts of water at pH 8 and a temperature of 70 C. This suspension is admixed with 67.9 parts of the chromium complex compound (containing 1 chromium atom per dyestuff molecule) of the azo dyestufi obtained from 4-chloro-2-diazol-hydroxybenzene-6-sulphonic acid and l-amino-8-hydroxynaphthalene-3,6 disulphonic acid, the pH being kept between 7 and 9 by the dropwise addition of a sodium carbonate solution. A dark-blue solution has formed afier 20 minutes at 70 80 C. The paper chromatogram shows that a uniform mixed complex has formed. The mixed complex is acylated within 1 hour at 40 C. and pH 6.5 7.5 with 22.0

mercapto-4-pyrrolidino-5-cyclohexenyl-l-acetamide, there is obtained 2,3,a-trimethyl-4-piperidino-phenylacetic acid and 3-methylmercapto-4-pyrrolidino-phenylacetamide, respectively.

zc. It is also possible to cyclize compounds corresponding to Formula 1 (except that R and R are replaced by hydrogen and the residue R to compounds of Formula 1) under acidcatalyzed reaction conditions in particular, preferably under the conditions of a FriedelCrafts reaction. In this connection, the residue R, can be present in the 5-position (in which case R H) or in the 6-position (in which case R, H). The reaction conditions are described in greater detail above, as well as in the literature. Suitable catalysts are, for example, acids, such as HCl, l-lBr, CF COOH, HF, polyphosphoric acid or Lewis acids, such as, e.g., AlCl AlBr SnCl.,, ZnCl BF ZrCl FeCl SbCl or TiCl,,, and suitable solvents are n-hexane, carbon disulfide, carbon tetrachloride, trichloroethylene, nitrobenzene, tetramethylenesulfone, nitroethane, polyphosphoric acid, glacial acetic acid, trifluoroacetic acid and/or acetic anhydride. The cyclization reaction is preferably conducted between 60 and 210.

The group CHX ,X in the residue R represents an aldehyde group which can optionally be present in a modified form, e.g., as thioaldehyde, Schiff base, acetal, thioacetal or aminal. The protective groups can be removed before conducting the cyclization. This can be accomplished by deketalization or transketalization in accordance with conventional methods; however, it is also possible to employ the blocked aldehyde component in the reaction, since the protective group is normally split under the acidic reaction conditions utilized during cyclization.

Starting compounds wherein R represents a (CH ),X group optionally containing one to two double bonds, or a 3- butenyl, 3-butynyl, 1,3-butadienyl, of 1-buten-3-ynyl group can likewise be alkylated to obtain compounds of Formula 1 intramolecularly under Friedel-Crafts conditions. These cyclization reactions take place rapidly and with good yields when X represents chlorine, bromine or iodine. lf X represents a hydroxy, alkoxy, acyloxy, sulfuric acid or sulfonic acid residue, there are likewise no difiiculties in the intramolecular Friedel-Crafts alkylation. In case X, and X in the residue R represent together or X represents OH, a1- kylated or acylated OH, the cyclization can also be accomplished with the aid of dehydrating agents, such as, for example, polyphosphoric acid, P 0 POCl PCl or SOCl with or without the addition of inert solvents, such as benzene, xylene, nitrobenzene or dichlorobenzene, at temperatures between preferably 80 and 300.

Thus, it is possible, for example, to cyclize 2-chloro-4-pyrrolidino-6-(3-formylpropyl)-phenylacetic acid to 2-chloro-4- pyrrolidino-7,8-dihydro-naphthyl-l-acetic acid, and 3-(4- bromobutyl)-4-piperidino-a-methyl-phenylacetamide to 4- piperidino-S ,6,7,8-tetrahydro-a-methyl-naphthalenel -acetamide.

zd. Compounds of the general Formula 1 wherein R and R together represent tetramethylene with one or two double bonds can be produced by eliminating, from compounds which otherwise correspond to Fonnula 1 (except that there is present a tetramethylene monosubstituted by X,, and optionally containing a double bond, or a tetramethylene disubstituted by X in place of the residues R, and R the substituent or substituents X in the form of HX,,, with the formation of one or two double bonds.

Such elimination reactions can be conducted without any difficulties; the respective dihydronaphthalene or naphthalene derivatives are obtained.

In case X Hal, this substituent can readily be eliminated as hydrogen halide with the formation of a double bond, under basic reaction conditions. Suitable bases are: alkali metal hydroxides, alkali metal carbonates, alcoholates, such as, e. g., potassium-tert.-butylate, amines, such as, e.g., dimethyl aniline, pyridine, collidine or quinoline. Suitable solvents, in this connection, are, for example, benzene, toluene, cyclohexane, methanol, dioxane, tetrahydrofuran, dimethyl formamide or tert.-butanol; however, the amines employed as the bases can also often be employed in excess as the solvent.

If X, represents a hydroxyl residue, the elimination process represents a step of splitting off water, which can be conducted in accordance with conventional methods. Agents which split off water, preferably employed in this connection, are POCl,-,, polyphosphoric acid, formic acid, perchloric acid, acetic anhydride, SOCl P 0 molecular sieves, sintered aluminum oxides, as well as other dehydrating oxides, such as SiO or also KHSO,,. The addition of a solvent can also be of advantage.

The process of splitting off water can also be conducted under acid catalysis by the azeotropic removal of the water which is formed. The elimination of alkyl, acyl, alkylsulfonyl and alkoxysulfonyloxy, -mercapto or -amino residues can be conducted under similar conditions. On the other hand, the elimination of the sulfonic acid residues, such as, for example, the elimination of the mesylates or tosylates, is conducted in a gentle manner by boiling in dimethyl formamide or dimethyl sulfoxide with alkali metal carbonates, such as, e.g., Li CO or with potassium acetate.

Thus, it is possible, for example, by splitting off HBr, to obtain from the diethylarnide of 3-chloro-4homopiperidino-5- bromo-S,o-dihydro-naphthalene-l-acetic acid the corresponding 3-chloro-4homopiperidino-naphthalene- 1 -ac etic acid diethylamide. Likewise, 2-nitro-4-piperidino-a-methyl- 7,8-dihydro-naphthyl-l-acetic acid can be obtained from 2- nitro-4-piperidino-5-hydroxy-a-methyl-5,6,7,B-tetrahydronaphthyl-l-acetic acid by splitting off H O. Furthermore, it is possible to produce 4-piperidino-naphthyl-l-acetic acid from 4-piperidino-5 ,8-dibromo-5 ,6,7,8-tetrahydro-naphthyll acetic acid, with 2 mols of HBr being split off.

ze. Compounds of Formula 1 are also obtained by eliminating, from a compound corresponding to Formula 1 (except that there is present, in place of the residues R and R a tetramethylene optionally containing a double bond and dis ubstituted by X and X in the 1,2- or l,4- or 3,4-position) each of the two substituents X-, and X with the formation of a double bond. This is done particularly well with metals, such as Zn, Zn-Cu, Na, Li or K, or with organometallic compounds, such as Grignard or organolithium compounds.

In particular, the elimination of vicinal dihalogenides, such as dichlorides, dibromides, or diiodides, as well as halohydrins, such as chloroor bromohydrin, or of vicinal haloesters, is accomplished as described in the literature, wherein X, represents, for example, Cl, Br, or I, and X represents acyloxy. These vicinal eliminations are preferably conducted with zinc in acetic acid, with the addition of sodium acetate, or in ethanol by boiling. The reaction times vary preferably between l0 minutes and several hours, and the reaction temperatures are between and 300. Suitable solvents are, for example, benzene, toluene, xylene, dichlorobenzene, ethylene glycol, diethylene glycol dimethyl ether or dimethyl formamide.

Thus, it is possible, for example, to react 4-piperidino-5,6-

dichloro-S,6,7,8-tetrahydro-naphthyll -acetic acid to 4- piperidino-7 ,S-dihydro-naphthyll -acetic acid; and 4- morpholino-7-chloro-8-hydroxy-7,8 -dihydro-a-ethylnaphthyl-l-acetic acid to 4-morpholino-a-ethyl-naphthyl-lacetic acid.

zf. A compound of Formula 1 can be converted into the acid addition salt thereof in a conventional manner by means of an acid. For this reaction, acids are employed which yield physiologically acceptable salts. It is thus possible to employ organic and inorganic acids, such as, for example, aliphatic, alicyclic, araliphatic, aromatic or heterocyclic, monoor polybasic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, oxalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, aminocarboxylic acids, sulfamic acid, benzoic acid, salicyclic acid, phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, 

2. A member as defined by claim 1 wherein R5 and R6 represent H; and A represents COOH.
 3. A member as defined by claim 1 wherein R4 and R5 together represent tetramethylene containing zero to two double bonds; and R3 and R6 each is H, or one of the residues R3 and R6 is F, Hal, OH, NO2, CN, R9, OR9, SR9, NR1-COR9, NR1R2, SO2NR1R2, SOR9 or SO2R9.
 4. A member as defined by claim 1 wherein R4 is H; one of the residues R5 and R6 is H and the other is F, Hal, R9, OR9 or SR9.
 5. A member as defined by claim 1 wherein A is COOH.
 6. A member as defined by claim 1 wherein R1 is H, methyl, ethyl or propyl.
 7. A member as defined by claim 1 wherein R2 is H.
 8. A member as defined by claim 1 wherein R4, R5 and R6 represent H.
 9. A member as defined by claim 1 wherein R2, R4, R5 and R6 represent H.
 10. A member as defined by claim 1 wherein R4 and R5 together represent -CH=CH-CH=CH-.
 11. A member as defined by claim 1 wherein R3 is SOR9 or SO2R9.
 12. A member as defined by claim 1 wherein R3 represents F, Cl, Br, R9, NH2 or NO2.
 13. A member as defined by claim 1 wherein R7 and R8 together represent tetramethylene, pentamethylene or hexamethylene.
 14. A member as defined in claim 1 wherein R1 is H, methyl, ethyl or propyl; R2 is H or methyl; R3 is Cl, Br, R9, NH2, NO2 or, when R4 and R5 together represent -CH=CH-CH=CH-, H; R4 and R5 represent H or together -CH=CH-CH=CH-; R6 is H, methyl, Cl or Br; R7 and R8 together represent tetramethylene, pentamethylene or hexamethylene and; A1 is H.
 15. A member as defined by claim 1 wherein R1 represents H, methyl, ethyl or propyl; R2 represents H or methyl; R3 represents Cl, Br, R9, NH2, NO2 or when R4 and R5 together represent -CH=CH-CH=CH-, H; R4 and R5 represent H or together -CH=CH-CH=CH-; R6 is H, methyl, Cl or Br; R7 and R8 together represent tetramethylene, pentamethylene or hexamethylene and, A1 is alkyl of one to six carbon atoms.
 16. A compound of claim 1, 3-methyl-4-piperidino-phenylacetic acid.
 17. A compound of claim 1, 3, Alpha -dimethyl-4-piperidino-phenylacetic acid.
 18. A compound of claim 1, 2,3, Alpha -trimethyl-4-piperidino-phenylacetic acid.
 19. A compound of claim 1, 2,3, Alpha -trimethyl-4-piperidino-phenylacetic acid ethyl ester.
 20. A compound of claim 1, 3-fluoro-4-piperidino- Alpha -methyl-phenylacetic acid.
 21. A compound of claim 1, 3-chloro-4-pyrrolidino- Alpha -methyl-phenylacetic acid.
 22. A compound of claim 1, 3-chloro-4-piperidino-phenylacetic acid.
 23. A compound of claim 1, 3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid.
 24. A compound of claim 1, 3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid methyl ester.
 25. A compound of claim 1, 3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid ethyl ester.
 26. A compound of claim 1, 3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid n-propyl ester.
 27. A compound of claim 1, 3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid n-butyl ester.
 28. A compound of claim 1, 3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid sec.-butyl ester.
 29. A compound of claim 1, 3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid n-hexyl ester.
 30. A compound of claim 1, 3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid 2-hexyl ester.
 31. A compound of claim 1, 3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid 3-hexyl ester.
 32. A compound of claim 1, 3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid n-octyl ester.
 33. A compound of claim 1, 3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid n-decyl ester.
 34. A compound of claim 1, 3-trifluoromethyl-4-piperidino- Alpha -methyl-phenylacetic acid.
 35. A compound of claim 1, 3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid cyclohexyl ester.
 36. A compound of claim 1, 3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid allyl ester.
 37. A compound of claim 1, 2-chloro-3, Alpha -dimethyl-4-piperidino-phenylacetic acid.
 38. A compound of claim 1, 2, Alpha -dimethyl-3-chloro-4-piperidino-phenylacetic acid.
 39. A compound of claim 1, 2, Alpha -dimethyl-3-chloro-4-piperidino-phenylacetic acid ethyl ester.
 40. A compound of claim 1, 3-bromo-4-pyrrolidino- Alpha -methyl-phenylacetic acid.
 41. A compound of claim 1, 3-bromo-4-piperidino-phenylacetic acid.
 42. A compound of claim 1, 3-methylmercapto-4-piperidino- Alpha -methyl-phenylacetic acid.
 43. A compound of claim 1, 3-bromo-4-piperidino- Alpha -methyl-phenylacetic acid.
 44. A compound of claim 1, 3-bromo-4-piperidino- Alpha -ethyl-phenylacetic acid.
 45. A compound of claim 1, 3-iodo-4-piperidino- Alpha -methyl-phenylacetic acid.
 46. A compound of claim 1, 3-nitro-4-pyrrolidino- Alpha -methyl-phenylacetic acid.
 47. A compound of claim 1, 3-nitro-4-piperidino- Alpha -methyl-phenylacetic acid.
 48. A compound of claim 1, 3-nitro-4-homopiperidino- Alpha -methyl-phenylacetic acid, cyclohexylamine salt.
 49. A compound of claim 1, 3-amino-4-pyrrolidino- Alpha -methyl-phenylacetic acid, cyclohexylamine salt.
 50. A compound of claim 1, 3-amino-4-piperidino-phenylacetic acid methyl ester.
 51. A compound of claim 1, 3-amino-4-piperidino- Alpha -methyl-phenylacetic acid.
 52. A compound of claim 1, 3-amino-4-piperidino- Alpha -methyl-phenylacetic acid methyl ester.
 53. A compound of claim 1, 3-amino-4-homopiperidino- Alpha -methyl-phenylacetic acid, cyclohexylamine salt.
 54. A compound of claim 1, 3-acetamido-4-piperidino- Alpha -methyl-phenylacetic acid.
 55. A compound of claim 1, 2,3-dichloro-4-piperidino- Alpha -methyl-phenylacetic acid.
 56. A compound of claim 1, 2,3-dichloro-4-piperidino- Alpha -methyl-phenylacetic acid ethyl ester.
 57. A compound of claim 1, 4-piperidino-naphthyl-1-aCetic acid.
 58. A compound of claim 1, 4-piperidino-naphthyl-1-acetic acid methyl ester hydrochloride.
 59. A compound of claim 1, 4-piperidino-naphthyl-1-acetic acid ethyl ester.
 60. A compound of claim 1, 4-piperidino- Alpha -methyl-naphthyl-1-acetic acid.
 61. A compound of claim 1, 4-piperidino- Alpha -methyl-naphthyl-1-acetic acid methyl ester.
 62. A compound of claim 1, 4-piperidino- Alpha -methyl-naphthyl-1-acetic acid ethyl ester.
 63. A compound of claim 1, 4-piperidino- Alpha -methyl-naphthyl-1-acetic acid n-propyl ester.
 64. A compound of claim 1, 4-piperidino- Alpha -methyl-naphthyl-1-acetic acid n-hexyl ester.
 65. A compound of claim 1, 4-piperidino- Alpha -methyl-naphthyl-1-acetic acid 2-hexyl ester.
 66. A compound of claim 1, 4-piperidino- Alpha -methyl-naphthyl-1-acetic acid 3-hexyl ester.
 67. A compound of claim 48, 4-piperidino- Alpha -methyl-naphthyl-1-acetic acid amide.
 68. A compound of claim 1, 2-methyl-4-piperidino-naphthyl-1-acetic acid.
 69. A compound of claim 1, 4-piperidino- Alpha -ethyl-naphthyl-1-acetic acid.
 70. A compound of claim 1, 2, Alpha -dimethyl-4-piperidino-naphthyl-1-acetic acid.
 71. A compound of claim 1, 4-piperidino- Alpha -methyl-5,6,7,8-tetrahydronaphthyl-1-acetic acid.
 72. A compound of claim 1, 3-chloro-4-piperidino-naphthyl-1-acetic acid.
 73. A compound of claim 1, (+)-3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid.
 74. A compound of claim 1, (-)-3-chloro-4-piperidino- Alpha -methyl-phenylacetic acid.
 75. A compound of claim 1, 3-hydroxy-4-piperidino- Alpha -methyl-phenylacetic acid.
 76. A compound of claim 1, 3-cyano-4-piperidino- Alpha -methyl-phenylacetic acid.
 77. A compound of claim 1, 3-sulfamoyl-4-piperidino- Alpha -methyl-phenylacetic acid.
 78. A compound of claim 1, 3-methoxy-4-piperidino- Alpha -methyl-phenylacetic acid.
 79. A compound of claim 1, 3-ethoxy-4-piperidino- Alpha -methyl-phenylacetic acid.
 80. A compound of claim 1, 3-ethylmercapto-4-piperidino- Alpha -methyl-phenylacetic acid.
 81. A compound of claim 1, 3-methylamino-4-piperidino- Alpha -methyl-phenylacetic acid.
 82. A compound of claim 1, 3-dimethylamino-4-piperidino- Alpha -methyl-phenylacetic acid.
 83. A compound of claim 1, 3-methylsufamoyl-4-piperidino- Alpha -methyl-phenylacetic acid.
 84. A compound of claim 1, 3-dimethylsulfamoyl-4-piperidino-Alpha -methyl-phenylacetic acid.
 85. A compound of claim 1, 3-methylsulfinyl-4-piperidino- Alpha -methyl-phenylacetic acid.
 86. A compound of claim 1, 3-ethylsulfinyl-4-piperidino- Alpha -methyl-phenylacetic acid.
 87. A compound of claim 1, 3-methylsulfonyl-4-piperidino- Alpha -methyl-phenylacetic acid.
 88. A compound of claim 1, 3-ethylsulfonyl-4-piperidino- Alpha -methyl-phenylacetic acid.
 89. A compound of claim 1, 3-chloro-4-piperidino- Alpha -ethyl-phenylacetic acid.
 90. A compound of claim 1, 3-amino-4-piperidino- Alpha -ethyl-phenylacetic acid.
 91. A compound of claim 1, 3-methyl-4-piperidino- Alpha -ethyl-phenylacetic acid.
 92. A compound of claim 1, 3-chloro-4-piperidino- Alpha -n-propyl-phenylacetic acid.
 93. A compound of claim 1, 3-bromo-4-piperidino- Alpha -n-propyl-phenylacetic acid.
 94. A compound of claim 1, 3-chloro-4-piperidino- Alpha , Alpha -dimethyl-phenylacetic acid.
 95. A compound of claim 1, 3-bromo-4-piperidino- Alpha , Alpha -dimethyl-phenylacetic acid.
 96. A compound of claim 1, 3-trifluoromethyl-4-pyrrolidino-Alpha -methyl-phenylacetic acid.
 97. A compound of claim 1, 3-amino-4-pyrrolidino- Alpha -methyl-phenylacetic acid.
 98. A compound of claim 1, 3, Alpha -dimethyl-4-pyrrolidino-phenylacetic acid.
 99. A compound of claim 1, 3-methylsulfinyl-4-pyrrolidino- Alpha -methyl-phenylacetic acid.
 100. A compound of claim 1, 3-methylsulfonyl-4-pyrrolidino-Alpha -methyl-phenylacetic acid.
 101. A compound of claim 1, 3-chloro-4-homopiperidino- Alpha -methyl-phenylacetic acid.
 102. A compound of claim 1, 3-bromo-4-homopiperidino- Alpha -methyl-phenylacetic acid.
 103. A compound of claim 1, 3-trifluoromethyl-4-homopiperidino-Alpha -methyl-phenylacetic acid.
 104. A compound of claim 1, 3-amino-4-homopiperidino- Alpha -methyl-phenylacetic acid.
 105. A compound of claim 1, 3-methylsulfinyl-4-homopiperidino-Alpha -methyl-phenylacetic acid.
 106. A compound of claim 1, 3-methylsulfonyl-4-homopiperidino-Alpha -methyl-phenylacetic acid.
 107. A compound of claim 1, (+)-3-bromo-4-piperidino- Alpha -methyl-phenylacetic acid.
 108. A compound of claim 1, (-)-3-bromo-4-piperidino- Alpha -methyl-phenylacetic acid.
 109. A compound of claim 1, (+)-3, Alpha -dimethyl-4-piperidino-phenylacetic acid.
 110. A compound of claim 1, (-)-3 Alpha -dimethyl-4-piperidino-phenylacetic acid.
 111. A compound of claim 1, (+)-3-amino-4-piperidino- Alpha -methyl-phenylacetic acid.
 112. A compound of claim 1, (-)-3-amino-4-piperidino- Alpha -methyl-phenylacetic acid.
 113. A compound of claim 1, (+)-3-trifluoromethyl-4-piperidino-Alpha -methyl-phenylacetic acid.
 114. A compound of claim 1, (-)-3-trifluoromethyl-4-piperidino-Alpha -methyl-phenylacetic acid.
 115. A compound of claim 1, (+)-3-chloro-4-pyrrolidino- Alpha -methyl-phenylacetic acid.
 116. A compound of claim 1, (-)-3-chloro-4-pyrrolidino- Alpha -methyl-phenylacetic acid.
 117. A compound of claim 1, (+)-3-chloro-4-homopiperidino- Alpha -methyl-phenylacetic acid.
 118. A compound of claim 1, (-)-3-chloro-4-homopiperidino- Alpha -methyl-phenylacetic acid.
 119. A compound of claim 1, methyl ester of 3-bromo-4-piperidino- Alpha -methyl-phenylacetic acid.
 120. A compound of claim 1, ethyl ester of 3-bromo-4-piperidino-Alpha -methyl-phenylacetic acid.
 121. A compound of claim 1, ethyl ester of 3, Alpha -dimethyl-4-piperidino-phenylacetic acid.
 122. A compound of claim 1, ethyl ester of 3-amino-4-piperidino-Alpha -methyl-phenylacetic acid.
 123. A compound of claim 1, n-propyl ester of 3-amino-4-piperidino- Alpha -methyl-phenylacetic acid.
 124. A compound of claim 1, ethyl ester of 3-fluoro-4-piperidino- Alpha -methyl-phenylacetic acid.
 125. A compound of claim 1, ethyl ester of 3-trifluoro-methyl-4-piperidino- Alpha -methyl-phenylacetic acid.
 126. A compound of claim 1, 3-chloro-4-piperidino- Alpha -methyl-naphthyl-1-acetic acid.
 127. A compound of claim 1, 3-amino-4-piperidino- Alpha -methyl-naphthyl-1-acetic acid.
 128. A compound of claim 1, 3, Alpha -dimethyl-4-piperidino-naphthyl-1-acetic acid.
 129. A compound of claim 1, 2-chloro-4piperidino- Alpha -methyl-naphthyl-1-acetic acid.
 130. A compound of claim 1, 2-amino-4-piperidino- Alpha -methyl-naphthyl-1-acetic acid.
 131. A compound of claim 1, 4-pyrrolidino- Alpha -methyl-naphthyl-1-acetic acid.
 132. A compound of claim 1, 4-homopiperidino- Alpha -methyl-naphthyl-1-acetic acid.
 133. A compound of claim 1, 4-piperidino- Alpha -methyl-5,6-dihydro-naphthyl-1-acetic acid.
 134. A compound of claim 1, 4-piperidino- Alpha -methyl-5,8-dihydro-naphthyl-1-acetic acid.
 135. A compound of claim 1, 4-piperidino- Alpha -methyl-7,8-dihydro-naphthyl-1-acetic acid.
 136. A compound of claim 1, 2,3-dibromo-4-piperidino- Alpha -methyl-phenYlacetic acid.
 137. A compound of claim 1, 2,3-dibromo-4-pyrrolidino- Alpha -methyl-phenylacetic acid.
 138. A compound of claim 1, 2,3-dichloro-4-homopiperidino- Alpha -methyl-phenylacetic acid.
 139. A compound of claim 1, propyl ester of 2,3-dichloro-4-piperidino- Alpha -methyl-phenylacetic acid.
 140. A compound of claim 1, methyl ester of 2,3-dichloro-4-piperidino- Alpha -methyl-phenylacetic acid.
 141. A compound of claim 1, 3,5-dichloro-4-piperidino- Alpha -methyl-phenylacetic acid.
 142. A compound of claim 1, 3-chloro-4-piperidino-5, Alpha -dimethyl-phenylacetic acid.
 143. A compound of claim 1, ethyl ester of 3,5-dichloro-4-piperidino- Alpha -methyl-phenylacetic acid.
 144. A compound of claim 1, ethyl ester of 3-chloro-4-piperidino-5, Alpha -dimethyl-phenylacetic acid. 